Processes for producing 7-isoindoline-quinolonecarboxylic acid derivative and its intermediate, as well as salt of 7-isoindoline-quinolonecarboxylic acid derivative, its hydrate and composition comprising the same as active ingredient

ABSTRACT

Processes for producing a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1] which is useful as an antibacterial agent, and an intermediate thereof:  
                 
 
     comprising reacting, in the presence of metallic palladium, an isoindoline-5-boronic acid, or of a 5-halogenoisoindoline, in the presence of a palladium catalyst, with a dialkoxyborane or an alkoxydiborane.

TECHNICAL FIELD

[0001] This invention relates to processes for producing a7-isoindoline-quinolonecarboxylic acid derivative represented by thegeneral formula [1] and its intermediate as well as a salt of7-isoindoline-quinolonecarboxylic acid derivative represented by thegeneral formula [1], its hydrate and a composition comprising the sameas an active ingredient:

[0002] wherein R¹ represents a hydrogen atom or a carboxyl-protectinggroup; R² represents a substituted or unsubstituted alkyl, alkenyl,cycloalkyl, aryl or heterocyclic group; R³ represents at least one groupselected from hydrogen atom, halogen atoms, substituted or unsubstitutedalkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitrogroup, cyano group, acyl groups, protected or unprotected hydroxylgroups and protected or unprotected or substituted or unsubstitutedamino groups; R⁴ represents at least one group selected from hydrogenatom, halogen atoms, substituted or unsubstituted alkyl, alkenyl,cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected orunprotected hydroxyl or imino groups, protected or unprotected orsubstituted or unsubstituted amino groups, alkylidene groups, oxo groupand groups each forming a cycloalkane ring with the carbon atom to whichR⁴ bonds; R⁵ represents a hydrogen atom, an amino-protecting group or asubstituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl,arylsulfonyl, acyl or aryl group; R⁶ represents a hydrogen atom, ahalogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthiogroup, a protected or unprotected hydroxyl or amino group or a nitrogroup; and A represents CH or C-R⁷ in which R⁷ represents a halogenatom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group ora protected or unprotected hydroxyl group.

BACKGROUND ART

[0003] As the process for producing a compound of the general formula[1], there has been known the process described in WO97/29102. That isto say, said publication describes that a compound of the generalformula [1] can be produced by subjecting a 5-halogenoisoindolinederivative represented by the following general formula [4] or its salt:

[0004] wherein R³, R⁴ and R⁵ have the same meanings as mentioned aboveand X¹ represents a halogen atom, to lithiation or Grignard reaction andthereafter to reaction with a trialkyl borate to form anisoindoline-5-boronic acid derivative represented by the followinggeneral formula [2c] or its salt:

[0005] wherein R³, R⁴ and R⁵ have the same meanings as mentioned aboveand R¹¹ represents a hydrogen atom or an alkyl group; and subsequentlyreacting the isoindoline-5-boronic acid derivative or its salt with a7-halogenoquinolonecarboxylic acid represented by the following generalformula [3b]:

[0006] wherein R¹, R², R⁶ and A have the same meanings as mentionedabove and X³ represents a halogen atom, in the presence of a palladiumcomplex such as bis(triphenylphosphine)-palladium(II) chloride,tetrakis(triphenylphosphine)-palladium(0) or the like.

[0007] Among the compounds of the general formula [1],(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylicacid represented by the formula:

[0008] (referred to hereinafter as T-3811) is a compound excellent inactivity against Gram-positive and Gram-negative bacteria and thedevelopment of a process for industrially producing the same has beendesired.

[0009] Moreover, T-3811 is low in solubility in the vicinity of neutral,so that the enhancement of solubility at a physiologically acceptable pHhas been desired.

DISCLOSURE OF THE INVENTION

[0010] In order to develop a process for industrially producing a7-isoindoline-quinolonecarboxylic acid derivative of the general formula[1] including T-3811, the present inventors have diligently maderesearch to find consequently that a coupling reaction between anisoindoline-5-boronic acid derivative represented by the followinggeneral formula [2]:

[0011] wherein R³, R⁴ and R⁵ have the same meanings as mentioned aboveand R⁸ and R⁹ represent hydrogen atoms or lower alkyl groups or form aring comprising the boron atom when taken together, and a 7-leavinggroup-substituted quinolone-carboxylic acid represented by the followinggeneral formula [3]:

[0012] wherein R¹, R², R⁶ and A have the same meanings as mentionedabove and x² represents a leaving group, can be easily carried out inthe presence of metallic palladium.

[0013] Furthermore, it has been found that an isoindoline-5-boronic acidderivative represented by the following general formula [2a]:

[0014] wherein R³, R⁴ and R⁵ have the same meanings as mentioned aboveand Z represents an alkylene group can easily be obtained not by theconventional borodation through lithiation or Grignard reaction but bythe reaction of a 5-halogenoisoindoline derivative represented by thefollowing general formula [4]:

[0015] wherein R³, R⁴, R⁵ and X¹ have the same meanings as mentionedabove, with a dialkoxyborane or an alkoxydiborane in the presence of apalladium catalyst, and further found that the compound of the generalformula [2a] can be applied, without being isolated, to the so-calledone-pot reaction by which the compound of the general formula [3] isreacted to produce a 7-isoindoline-quinolonecarboxylic acid derivativerepresented by the general formula [1].

[0016] Also, the present inventors have found that a1-alkylisoindoline-5-boronic acid derivative represented by thefollowing general formula [2b]:

[0017] wherein R^(4a) represents an alkyl group and R⁵, R⁸ and R⁹ havethe same meanings as mentioned above is an excellent intermediate forproducing a 7-isoindoline-quinolone-carboxylic acid derivativerepresented by the following general formula [1a]:

[0018] wherein R^(4a), R¹, R², R⁵, R⁶ and A have the same meanings asmentioned above among the compounds of the general formula [1].

[0019] Moreover, it has been found that a 1-alkyl-5-halogenoisoindolinederivative represented by the following general formula [4a]:

[0020] wherein R^(4a), R⁵ and X¹ have the same meanings as mentionedabove, can be produced by using a 4-halogenobenzylamine derivative asthe starting material.

[0021] Furthermore, it has been found that as the process for producinga 7-bromo-quinolonecarboxylic acid derivative represented by thefollowing general formula [3a] which is a useful intermediate forproducing T-3811:

[0022] wherein R^(1b) represents a carboxyl-protecting group; R^(7a)represents a substituted or unsubstituted alkyl group; and R^(2a)represents a substituted or unsubstituted alkyl, cycloalkyl, aryl orheterocyclic group, a process in which a 2,4-dibromo-3-hydroxybenzoicacid ester is used as the starting material and which is through variousintermediates as mentioned hereinafter is an excellent industrialproduction process.

[0023] As mentioned above, the present inventors have diligently maderesearch on 7-isoindoline-quinolone-carboxylic acid derivativesrepresented by the general formula [1] including T-3811 andintermediates for producing the same and have accomplished thisinvention.

[0024] In addition, the present inventors have examined various salts ofT-3811 which have never been known, and have consequently found thatamong them, methanesulfonate of T-3811 is much higher in solubility at aphysiologically acceptable pH than the other salts of T-3811 and furtherthat T-3811 methanesulfonate hydrate has no polymorphism and is good instability against humidity, and hence, it has a very high usefulness asa composition, particularly as a starting material for preparation,whereby this invention has been accomplished.

[0025] In the present specification, unless otherwise specified, theterm “halogen atom” means fluorine atom, chlorine atom, bromine atom oriodine atom; the term “alkyl group” means a straight or branched chainC₁₋₁₀ alkyl group, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octylor the like; the term “alkenyl group” means a straight or branched chainC₂₋₁₀ alkenyl group, for example, vinyl, allyl, isopropenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl or the like; the term “alkylidenegroup” means a straight or branched chain C₁₋₁₀ alkylidene group, forexample, methylene, ethylidene, propylidene, isopropylidene, butylidene,hexylidene, octylidene or the like; the term “cycloalkyl group” means aC₃₋₆ cycloalkyl group, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or the like; the term “cycloalkane ring” means aC₃₋₆ cycloalkane ring, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane or the like; the term “alkylene group” means astraight or branched chain C₁₋₁₀ alkylene group, for example, ethylene,trimethylene, tetramethylene, 1,2-dimethylethylene,1,3-dimethyl-trimethylene, 1,1,2,2-tetramethylethylene or the like; theterm “alkoxy group” means a straight or branched chain C₁₋₁₀ alkoxygroup, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy or the like; the term “alkoxycarbonyl group” means analkoxy-CO- group (in which the alkoxy represents the above-mentionedstraight or branched chain C₁₋₁₀ alkoxy group), for example,methoxy-carbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl or the like; the term “alkylaminogroup” means a straight or branched chain C₁₋₁₀ alkyl group-substitutedamino group, for example, methylamino, ethylamino, propylamino,butylamino, pentylamino, hexylamino, dimethylamino, diethylamino,methylethylamino, dipropylamino, dibutylamino, dipentylamino or thelike; the term “alkylthio group” means a straight or branched chainC₁₋₁₀ alkylthio group, for example, methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tertbutylthio,pentylthio, hexylthio, heptylthio, octylthio or the like; the term“alkylsulfonyl group” means a straight or branched C₁₋₁₀ alkylsulfonylgroup, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl,octylsulfonyl or the like; the term “acyl group” means, for example, aformyl group, a straight or branched chain C₂₋₅ alkanoyl group such asacetyl, ethylcarbonyl or the like or an aroyl group such as benzoyl,naphthylcarbonyl or the like; the term “aryl group” means, for example,a phenyl or naphthyl group; the term “arylsulfonyl group” means, forexample, a phenylsulfonyl or naphthylsulfonyl group; the term “aralkylgroup” means, for example, a benzyl, phenethyl, diphenylmethyl ortriphenylmethyl group; the term “heterocyclic group” means a 4-membered,5-membered or 6-membered ring containing at least one hetero atomselected from oxygen atom, nitrogen atom and sulfur atom as the heteroatom forming the ring or a condensed ring thereof, for example, anoxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl,benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl ormorpholinyl group.

[0026] Moreover, in the present specification, the term “lower” means 1to 5 carbon atoms, provided that the term “lower” in the term “loweralkenyl” means 2 to 5 carbon atoms.

[0027] The protecting groups for amino group, lower alkylamino group andimino group include all conventional groups usable as amino-protectinggroups, and there are mentioned, for example, acyl groups such astrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-,tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl,benzoyl, tert-amyloxycarbonyl, tertbutoxycarbonyl,p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, pivaloyl and the like;ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl and thelike; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthioand the like; alkyl- or aryl-sulfonyl groups such as methanesulfonyl,p-toluenesulfonyl and the like; di-lower alkylamino-lower alkylidenegroups such as N,N-dimethylaminomethylene and the like; ar-loweralkylidene groups such as benzylidene, 2-hydroxybenzylidene,2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and thelike; nitrogen-containing heterocyclic alkylidene groups such as3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups suchas cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- or di-ar-loweralkyl-phosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryland the like; oxygen-containing heterocyclic alkyl groups such as5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; substituted silylgroups such as trimethylsilyl and the like; etc.

[0028] The protecting groups for the carboxyl group include allconventional groups usable as carboxyl-protecting groups and there arementioned, for example, lower alkyl groups such as methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and thelike; aryl groups such as phenyl, naphthyl and the like; ar-lower alkylgroups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl,p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-loweralkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl,p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like;oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl,2-tetrahydrofuranyl and the like; halogeno-lower alkyl groups such as2,2,2-trichloroethyl and the like; lower alkylsilyl-lower alkyl groupssuch as 2-(trimethylsilyl)ethyl and the like; acyloxy-lower alkyl groupssuch as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and thelike; nitrogen-containing heterocyclic-lower alkyl groups such asphthalimidomethyl, succinimidomethyl and the like; cycloalkyl groupssuch as cyclohexyl and the like; lower alkoxy-lower alkyl groups such asmethoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl andthe like; ar-lower alkoxy-lower alkyl groups such as benzyloxymethyl andthe like; lower alkylthio-lower alkyl groups such as methylthiomethyl,2-ethylthioethyl and the like; arylthio-lower alkyl groups such asphenylthiomethyl and the like; lower alkenyl groups such as1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like;substituted silyl groups such as trimethylsilyl, triethylsilyl,triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, diphenylmethylsilyl,tert-butylmethoxyphenylsilyl and the like.

[0029] The protecting groups for the hydroxyl group include allconventional groups usable as hydroxyl-protecting groups and there arementioned, for example, acyl groups such as benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxy-carbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl,ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl,isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,2-(trimethylsilyl)-ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl,1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl and the like; lower alkyl groups such as methyl,tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like;lower alkenyl groups such as allyl and the like; ar-lower alkyl groupssuch as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl,trityl and the like; oxygen-containing and sulfur-containingheterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl and the like; lower alkoxy- and loweralkylthio-lower alkyl groups such as methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyland the like; lower alkyl-and aryl-sulfonyl groups such asmethanesulfonyl, p-toluenesulfonyl and the like; substituted silylgroups such as trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like; etc.

[0030] The substituent of the alkyl, alkenyl, cycloalkyl, aryl orheterocyclic group for R²; the substituent of the alkyl, alkenyl,cycloalkyl, aryl, alkoxy, alkylthio or amino group for R³; thesubstituent of the alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy,alkylthio or amino group for R⁴; the substituent of the alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group for R⁵; thesubstituent of the alkyl, alkoxy or alkylthio group for R⁶; thesubstituent of the alkyl, alkoxy or alkylthio group for R⁷; and thesubstituent of the alkyl for R^(7a) include halogen atoms, cyano group,protected or unprotected carboxyl groups, protected or unprotectedhydroxyl groups, protected or unprotected amino groups, protected orunprotected lower alkylamino groups, lower alkyl groups, lower alkoxygroups, lower alkoxycarbonyl groups, aryl groups, cycloalkyl groups,lower alkenyl groups and halogen atom-substituted lower alkyl groups,and the R², R³, R⁴, R⁵, R⁶, R⁷ and R^(7a) groups may be substituted byone or two or more of these groups.

[0031] Moreover, as the substituent of the alkyl for R^(7a), a halogenatom is preferable.

[0032] The ring comprising the boron atom which R⁸ and R⁹ form whentaken together includes 5-membered to 8-membered rings containing atleast one hetero atom selected from oxygen atom and nitrogen atom as thehetero atom forming the ring and condensed rings thereof, for example,1,3,2-dioxaborolane, 1,3,2-dioxaborinane, 1,3,5,2-dioxazaborinane,1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocane, 1,3,6,2-dioxazaborocaneand the like.

[0033] The leaving group for X² includes halogen atoms such as chlorineatom, bromine atom, iodine atom and the like; halogen-substituted orunsubstituted alkylsulfonyloxy groups such as methylsulfonyloxy,trifluoromethylsulfonyloxy and the like; and arylsulfonyloxy groups suchas p-fluorophenylsulfonyloxy and the like.

[0034] As the alkyl group for R^(4a), a lower alkyl group is preferable.

[0035] I. Process for Producing Compound of the General Formula [1] andProcess for Producing Compound of the General Formula [2a]

Production Process IA

[0036]

Production Process IB

[0037]

[0038] wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, X¹, X², A and Z have thesame meanings as mentioned above.

[0039] The compounds of the general formulas [1], [2], [2a], [3], [4],[5a] and [5b] may be in the form of salts. As the salts, there can bementioned usually known salts at basic groups such as amino group andthe like and at acidic groups such as hydroxyl group, carboxyl group andthe like. As the salts at basic groups, there can be mentioned, forexample, salts with mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid and the like; salts with organic carboxylic acidssuch as tartaric acid, formic acid, lactic acid, citric acid,trichloroacetic acid, trifluoroacetic acid and the like; and salts withsulfonic acids such as methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonicacid and the like. Moreover, the salts at acidic groups, there can bementioned, for example, salts with alkali metals such as sodium,potassium and the like; salts with alkaline earth metals such ascalcium, magnesium and the like; salts with ammonium; salts withnitrogen-containing organic bases such as trimethylamine, triethylamine,tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylmorpholine, diethylamine, dicyclohexylamine, procaine,dibenzylamine, N-benzyl-b-phenethylamine, 1-ephenamine,N,N′-dibenzylethylenediamine and the like; etc.

Production Process IA

[0040] (1) Process for Producing Compound of the General Formula [1] orits Salt

[0041] The compound of the general formula [1] or its salt can beproduced by subjecting a compound of the general formula [2] or its saltand a compound of the general formula [3] or its salt to couplingreaction using metallic palladium in the presence or absence of a base.

[0042] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andincludes, for example, water; alcohols such as methanol, ethanol,propanol and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as methylenechloride, chloroform, dichloroethane and the like; ethers such asdioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether,dimethyl Cellosolve and the like; esters such as ethyl acetate, butylacetate and the like; ketones such as acetone, methyl ethyl ketone andthe like; nitrites such as acetonitrile and the like; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like; etc. These solvents may be usedin admixture.

[0043] The base which is used, if desired, in this reaction includes,for example, potassium acetate, sodium hydrogencarbonate, sodiumcarbonate, potassium carbonate, triethylamine and the like. The amountof the base used is at least equal to the molar amount of, preferably 1to 3 moles per mole of, the compound of the general formula [3] or itssalt.

[0044] The metallic palladium used in this reaction includes, forexample, palladium-activated carbon, palladium black and the like. Theamount of the metallic palladium used is at least 0.00001 mole,preferably 0.001 to 0.05 mole, per mole of the compound of the generalformula [3] or its salt.

[0045] The amount of the compound of the general formula [2] or its saltused is at least equal to the molar amount of, preferably 1.0 to 1.5moles per mole of, the compound of the general formula [3] or its salt.

[0046] This coupling reaction may be usually carried out in anatmosphere of an inert gas (for example, argon, nitrogen) at 50-170° C.for 1 minute to 24 hours.

[0047] Incidentally, the compound of the general formula [3] or its saltcan be produced by, for example, the method described in WO97/29102.

Production Process IIA

[0048] (2.1) Process for Producing Compound of the General Formula [2a]or its Salt

[0049] The compound of the general formula [2a] or its salt can beproduced by reacting a compound of the general formula [4] or its saltwith a dialkoxyborane of the general formula [5a] or an alkoxydiboraneof the general formula [5b] in the presence or absence of a base using apalladium catalyst selected from metallic palladium, palladium salts andpalladium complexes.

[0050] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aromatic hydrocarbons such as benzene, toluene, xylene and thelike; aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitriles such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxideand the like; etc. These solvents may be used in admixture.

[0051] The base which is used, if desired, in this reaction includes,for example, potassium acetate, potassium tert-butoxide,diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene,tributylamine, triethylamine and the like. The amount of the base usedis at least equal to the molar amount of, preferably 1 to 3 moles permole of, the compound of the general formula [4] or its salt.

[0052] The metallic palladium used in this reaction includes, forexample, metallic palladium such as palladium-activated carbon,palladium black and the like; the palladium salt includes, for example,inorganic palladium salts such as palladium chloride and the like andorganic palladium salts such as palladium acetate and the like; and thepalladium complex includes, for example, organic palladium complexessuch as tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)-palladium(II) chloride,1,1′-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and thelike. The amount of a palladium catalyst selected from metallicpalladium, palladium salt and palladium complex used may be at least0.00001 mole, preferably 0.001 to 0.05 mole, per mole of the compound ofthe general formula [4] or its salt.

[0053] The dialkoxyborane which is used in this reaction includes, forexample, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, catecholborane and thelike, and the alkoxydiborane includes, for example,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolaneand the like.

[0054] The amount thereof used is at least equal to the molar amount of,preferably 1.0 to 1.5 moles per mole of, the compound of the generalformula [4] or its salt.

[0055] This reaction may be carried out in an atmosphere of an inert gas(for example, argon, nitrogen) at 0-150° C., preferably 80-110° C., for1-24 hours.

[0056] (2.2) Process for Producing Compound of the General Formula [1]or its Salt

[0057] The compound of the general formula [1] or its salt can beproduced by adding the compound of the general formula [2a] or its saltproduced in the above (2.1) without isolation to the reaction mixtureand, if necessary, additionally adding a palladium catalyst, addingthereto the compound of the general formula [3] or its salt in thepresence or absence of a base in an atmosphere of an inert gas (forexample, argon, nitrogen), and further subjecting them to reaction.

[0058] When the compounds of the general formulas [2], [2a], [3] and [4]or their salts in the above-mentioned production process have isomers(for example, optical isomers, geometric isomers, tautomers and thelike), these isomers can be used, and their solvates, hydrates andcrystals of various forms can be used.

[0059] Furthermore, the amino groups of the compounds of the generalformulas [2], [2a], [3] and [4] or their salts can be previouslyprotected with a conventional protecting group and the protecting groupcan be removed in a manner known per se after the reaction.

[0060] The thus produced compound of the general formula [1] or its saltcan be isolated and purified in at least one conventional manner such asextraction, crystallization, column chromatography or the like.

[0061] Among the compounds of the general formula [1] produced by theprocess of this invention, there can be mentioned, as preferablecompounds, compounds of the general formula [1] wherein R² is asubstituted or unsubstituted cycloalkyl group; R³ is a hydrogen atom, ahalogen atom or an alkyl group; R⁴ is a hydrogen atom or an alkyl group;R⁵ is a hydrogen atom or an alkyl group; and A is CH or C-R⁷ in which R⁷is a halogen atom, a halogen-substituted or unsubstituted lower alkyl orlower alkoxy group. As representative compounds, there are mentioned,for example, the following compounds:

[0062]1-cyclopropyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0063]8-chloro-1-cyclopropyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0064]1-cyclopropyl-8-fluoro-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0065]1-cyclopropyl-7-(isoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0066]1-cyclopropyl-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0067]1-cyclopropyl-8-difluoromethoxy-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0068]1-cyclopropyl-7-(isoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0069]7-(7-chloroisoindolin-5-yl)-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0070]1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0071]1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0072]1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0073]1-cyclopropyl-8-difluoromethoxy-7-(7-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0074]1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0075]1-cyclopropyl-8-methoxy-7-(7-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0076]1-cyclopropyl-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0077]1-cyclopropyl-8-methyl-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0078]1-cyclopropyl-8-methoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0079]1-cyclopropyl-8-difluoromethoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0080]1-cyclopropyl-7-(2-methylisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0081](±)-1-cyclopropyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0082](±)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0083](+)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0084](−-)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0085](±)-1-cyclopropyl-8-methoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0086](+)-1-cyclopropyl-8-methoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0087](−)-1-cyclopropyl-8-methoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0088](±)-1-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0089](+)-1-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0090](−)-1-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0091]1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0092]1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0093]1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0094]1-cyclopropyl-8-difluoromethoxy-7-(4-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0095]1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0096]1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0097]1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0098]1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0099]1-cyclopropyl-8-difluoromethoxy-7-(6-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0100]1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0101]1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0102]1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0103]1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

[0104]1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, and

[0105]1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

[0106] Furthermore, among the compounds of the general formula [2a]produced by the process of this invention, there can be mentioned, aspreferable compounds, compounds of the general formula [2a] wherein R³is a hydrogen atom, a halogen atom or an alkyl group; R⁴ is a hydrogenatom or an alkyl group; R⁵ is a hydrogen atom or an alkyl group; and Zis 1,1,2,2-tetramethylethylene, and as representative compounds, thereare mentioned, for example, the following compounds:

[0107] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0108]7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0109]7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0110]7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0111]2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0112]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0113](±)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0114](+)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0115] (−)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0116]4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0117] 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline, and

[0118]4,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

[0119] II. Process for Producing 1-alkylisoindoline-5-boronic AcidDerivative

Production Process IIA

[0120]

[0121] wherein R^(4a), R⁵, R⁸, R⁹ and X¹ have the same meanings asmentioned above, R^(5a) represents a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, and R¹⁰represents a hydrogen atom or a carboxyl-protecting group.

[0122] The compounds of the general formulas [2b], [4a], [6], [7], [8],[9] and [10] can also be used in the form of salts, and as the salts,there can be mentioned usually known salts at basic groups such as aminogroup and the like and at acidic groups such as hydroxyl group, carboxylgroup and the like. The salt at basic group includes, for example, saltswith mineral acids such as hydrochloric acid, hydrobromic acid, sulfuricacid and the like; salts with organic carboxylic acids such as tartaricacid, formic acid, lactic acid, citric acid, trichloroacetic acid,trifluoroacetic acid and the like; and salts with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid and the like.Furthermore, the salt at acidic group includes, for example, salts withalkali metals such as sodium, potassium and the like; salts withalkaline earth metals such as calcium, magnesium and the like; saltswith ammonium; salts with nitrogen-containing organic bases such astrimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, dicyclohexylamine, procaine, dibenzylamine,N-benzyl-b-phenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamineand the like; etc.

[0123] (1) Process for Producing Compound of the General Formula [9] orits Salt

[0124] The compound of the general formula [9] or its salt can beproduced by reacting a compound of the general formula [10] or its saltwith carbon dioxide, a halogenated formic acid ester or a carbonic acidester in the presence of a base.

[0125] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; ethers such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran, dioxane and the like; etc. These solvents may be usedin admixture.

[0126] The base which is used in this reaction includes, for example,alkyl metal or aryl metal reagents such as n-butyllithium,tert-butyllithium, phenyllithium, methyllithium and the like; and amidebases such as lithium diisopropylamide, lithium bistrimethylsilylamideand the like.

[0127] The halogenated formic acid ester includes, for example, methylchloroformate, ethyl chloroformate and the like.

[0128] The carbonic acid ester includes, for example, dimethylcarbonate, diethyl carbonate, diphenyl carbonate and the like.

[0129] The amounts of the base and carbon dioxide, halogenated formicacid ester or carbonic acid ester used are at least 2 moles, preferably2 to 3 moles, per mole of the compound of the general formula [10] orits salt.

[0130] This reaction may be usually carried out at −70 to 20° C.,preferably −50 to 0° C., for 10 minutes to 24 hours.

[0131] The obtained compound of the general formula [9] or its salt maybe used as it is without isolation in the subsequent reaction.

[0132] (2) Process for Producing Compound of the General Formula [8] orits Salt

[0133] The compound of the general formula [8] or its salt can beproduced by subjecting the compound of the general formula [9] or itssalt to halogenation reaction.

[0134] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, carboxylic acids such as acetic acid and the like; halogenatedhydrocarbons such as carbon tetrachloride and the like; inorganic acidssuch as sulfuric acid, hydrochloric acid and the like; water; etc. Thesesolvents may be used in admixture.

[0135] The halogenating agent which is used in this reaction includes,for example, halogens such as chlorine, bromine, iodine and the like;organic halogen compounds such as N-bromosuccinimide, halogenatedisocyanuric acids such as sodium N-bromoisocyanurate and the like; etc.

[0136] The amount of the halogenating agent used is at least equal tothe molar amount of, preferably 1 to 1.5 moles per mole of, the compoundof the general formula [9] or its salt.

[0137] This reaction may be carried out at −10 to 100° C., preferably 0to 30° C., for 10 minutes to 24 hours.

[0138] The obtained compound of the general formula [8] or its salt maybe used as it is without isolation in the subsequent reaction.

[0139] (3) Process for Producing Compound of the General Formula [4a] orits Salt

[0140] The compound of the general formula [4a] or its salt can beproduced by reducing the compound of the general formula [8] or its saltto produce a compound of the general formula [6] or its salt andthereafter subjecting the compound of the general formula [6] or itssalt to ring-closing reaction or alternatively by ring-closing thecompound [8] or its salt to produce a compound of the general formula[7] or its salt and thereafter subjecting the compound of the generalformula [7] or its salt to reduction reaction.

[0141] The solvent which is used in this reduction reaction may be anysolvent as far as it does not adversely affect the reaction, andincludes, for example, alcohols such as methanol, ethanol, isopropanoland the like; ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like;nitrites such as acetonitrile and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxideand the like; water; etc. These solvents may be used in admixture.

[0142] The reducing agent which is used in this reaction includes, forexample, alkali metals such as lithium, sodium, potassium and the like;alkaline earth metals such as magnesium, calcium and the like; metalsand their salts such as zinc, aluminum, chromium, titanium, iron,samarium, selenium, sodium hydrosulfite and the like; metal hydridessuch as diisobutylaluminum hydride, trialkylaluminum hydride, tinhydride compound, hydrosilane and the like; borohydride complexcompounds such as sodium borohydride, lithium borohydride, potassiumborohydride, calcium borohydride and the like; aluminum hydride complexcompounds such as lithium aluminum hydride and the like, etc.; boranes;alkylboranes; and the like.

[0143] The amount of the reducing agent used in this reaction is varieddepending upon the kind of the reducing agent; however, at least 0.25mole is required and, for example, in the case of the boron hydridecomplex compound, the above amount is at least 0.25 mole, preferably0.25 to 2 moles, per mole of the compound of the general formula [8] or[7] or its salt.

[0144] This reaction may be carried out usually at −20 to 100° C.,preferably 0 to 50° C., for 10 minutes to 24 hours.

[0145] The solvent which is used in this ring-closing reaction may beany solvent as far as it does not adversely affect the reaction, andincludes, for example, ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like;nitriles such as acetonitrile and the like, amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxideand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; water; etc. These solvents may be used in admixture.

[0146] When the compound of the general formula [8] or its salt issubjected to ring-closing reaction to produce a compound of the generalformula [7] or its salt, or when the compound of the general formula [6]or its salt is subjected to activation of its hydroxyl group andthereafter to ring-closing reaction to produce a compound of the generalformula [4a] or its salt, the base which is if desired used includes,for example, sodium hydroxide, potassium hydroxide, sodiumtert-butoxide, potassium tert-butoxide, sodium hydride and the like, andthe amount of the base used is at least equal to the molar amount of,preferably 1 to 1.5 moles per mole of, the compound of the generalformula [8] or [6] or its salt.

[0147] Furthermore, as the catalyst which is if desired used, a usuallyknown phase transfer catalyst of quaternary ammonium salt is used;however, preferable are tetra-n-butylammonium bromide,tetra-n-butylammonium hydrogen-sulfate and the like. The amount of thecatalyst used is 0.01 to 0.2 mole per mole of the compound of theformula [8] or [6] or its salt.

[0148] This reaction may be carried out at usually 0 to 100° C.,preferably 0 to 30° C., for 10 minutes to 24 hours.

[0149] The obtained compound of the general formula [4a] or its salt maybe used as it is without isolation in the subsequent reaction.

[0150] (4) Process for Producing Compound of the General Formula [2b] orits Salt

[0151] The compound of the general formula [2b] or its salt can beproduced by subjecting the compound of the general formula [4a] or itssalt to borodation.

[0152] Specifically, according to, for example, the method described inJikken Kagaku Koza, 4th edition, Vol. 24, pages 61-90 (1992), it can beobtained by subjecting a compound of the formula [4b] or its salt tolithiation or Grignard reaction and thereafter to reaction with atrialkyl borate.

[0153] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; ethers such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran, dioxane and the like; etc. These solvents may be usedin admixture.

[0154] The lithiating agent which is used in this reaction includes, forexample, alkyl metal reagents such as n-butyllithium, tert-butyllithium,phenyllithium, methyllithium and the like; and amide bases such aslithium diisopropylamide, lithium bistrimethylsilylamide and the like.Moreover, the Grignard reagent can be obtained by reacting metallicmagnesium with the compound represented by the general formula [4a] orits salt.

[0155] The trialkyl borate which is used in this reaction includes, forexample, trimethyl borate, triethyl borate, triisopropyl borate,tributyl borate and the like.

[0156] The amount of the lithionizing agent, metallic magnesium ortrialkyl borate used is at least equal to the molar amount of,preferably 1 to 2 moles per mole of, the compound of the general formula[4a] or its salt.

[0157] This reaction may be carried out usually at −70 to 50° C.,preferably −60 to 0° C., for 10 minutes to 24 hours.

[0158] The obtained compound of the general formula [2b] or its salt maybe used as it is without isolation in the subsequent reaction.

[0159] The thus obtained compound of the general formula [2b] or itssalt can be subjected to, for example, protection or deprotection to beconverted to the other compound of the general formula [2b] or its salt.

[0160] When the compounds of the general formula [2b], [4a], [6], [7],[8], [9] and [10] or their salts in the above-mentioned productionprocess have isomers (for example, optical isomers, geometrical isomers,tautomers and the like), these isomers can be used, and their solvates,hydrates and crystals of various forms can also be used.

[0161] When the compounds of the general formulas [4a], [6], [7], [8],[9] and [10] or their salts have an amino group, a hydroxyl group or acarboxyl group, it is also possible to previously protect these groupswith a conventional protecting group and remove the protecting groupafter the reaction in a manner known per se.

[0162] Next, the process for producing a compound of the general formula[1a] or its salt using the compound of the general formula [2b] or itssalt as the starting material is explained.

Production Process IIB

[0163]

[0164] wherein R¹, R², R^(4a), R⁵, R⁶, R⁸, R⁹, X³ and A have the samemeanings as mentioned above.

[0165] The compound of the general formula [1a] or its salt can beobtained by subjecting a compound of the general formula [3b] or itssalt and the compound of the general formula [2b] or its salt tocoupling reaction using a palladium complex catalyst in the presence orabsence of a base.

[0166] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, water; alcohols such as methanol, ethanol, propanol and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxideand the like; etc. These solvents may be used in admixture.

[0167] The base which is used, if desired, in this reaction includes,for example, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, triethylamine and the like.

[0168] The palladium complex catalyst which is used in this reactionincludes, for example, inorganic palladium salts such as palladiumchloride and the like; organic palladium salts such as palladium acetateand the like; and organic palladium complexes such astetrakis(triphenyl-phosphine)palladium(0),bis(triphenylphosphine)-palladium(II) chloride,1,1′-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and thelike.

[0169] The amount of the compound of the general formula [2b] or itssalt used is at least equal to the molar amount of, preferably 1.0 to1.5 moles per mole of, the compound of the general formula [3b] or itssalt.

[0170] This coupling reaction may be carried out usually in anatmosphere of an inert gas (for example, argon, nitrogen) at 50 to 170°C. for 1 minute to 24 hours.

[0171] The salt of the compound of the general formula [1a] includes,for example, the same salts as those mentioned as to the compounds ofthe general formulas [2b], [4a], [6], [7], [8], [9] and [10].

[0172] The compound of the general formula [3b] or its salt can beproduced by, for example, the method described in WO97/29102.

[0173] III. Process for Producing 1-alkyl-5-halogenoisoindolineDerivative

Production Process IIIA

[0174]

[0175] wherein R^(4a), R⁵ and X¹ have the same meanings as mentionedabove; R^(5b), R^(5c) and R^(5d) may be the same or different and eachrepresents an alkyl group; and Y represents a leaving group.

[0176] The leaving group for Y includes, for example, halogen atoms;lower alkylsulfonyloxy groups such as methylsulfonyloxy,ethylsulfonyloxy, isopropylsulfonyloxy and the like; arylsulfonyloxygroups such as phenylsulfonyloxy, naphthylsulfonyloxy and the like; etc.

[0177] Furthermore, as the alkyl groups for R^(5b), R^(5c) and R^(5d),lower alkyl groups such as methyl group and the like are preferable.

[0178] The compounds of the general formulas [12] and [11] can also beconverted to their salts, and as the salts, there can be mentionedusually known salts at basic groups such as amino group and the like. Asthe salts at the basic groups, there can be mentioned, for example,salts with mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid and the like; salts with organic carboxylic acids such astartaric acid, formic acid, lactic acid, citric acid, trichloroaceticacid, trifluoroacetic acid and the like; salts with sulfonic acids suchas methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid and the like; etc.

[0179] Furthermore, the salts of the compounds of the general formulas[6] and [4a] in the present production process include the same salts asmentioned as to Production Process IIA.

[0180] (1) Process for Producing Compound of the General Formula [6] orits Salt

[0181] The compound of the general formula [6] or its salt can beproduced by reacting the compound of the general formula [12] or itssalt with a formaldehyde or its derivative in the presence of anaryllithium.

[0182] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; ethers such as diethyl ether, n-dibutyl ether,1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like. Thesesolvents may be used in admixture.

[0183] The aryllithium which is used in this invention includes, forexample, phenyllithium, biphenyllithium, naphthyllithium and the like.

[0184] The formaldehyde or its derivative includes, for example,formaldehyde, paraformaldehyde, trioxane and the like.

[0185] The amounts of the aryllithium and the formaldehyde or itsderivative used are at least 2 moles, preferably 2 to 5 moles, per moleof the compound of the general formula [12] or its salt.

[0186] This reaction may be carried out at usually −70 to 50° C.,preferably −30 to 30° C., for 10 minutes to 24 hours.

[0187] The obtained compound of the general formula [6] or its salt maybe used as it is without isolation in the subsequent reaction.

[0188] Moreover, the amino-protecting group may be subjected toelimination reaction after the reaction and a new amino-protecting groupmay be introduced.

[0189] (2) Process for Producing Compound of the General Formula [11] orits Salt

[0190] The compound of the general formula [11] or its salt can beproduced by reacting the compound of the general formula [6] or its saltwith a halogenating agent, a sulfonylating agent or the like in thepresence or absence of a base.

[0191] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; halogenated hydrocarbons such as methylene chloride, chloroformand the like; ethers such as tetrahydrofuran, 1,2-dimethoxyethane,dioxane and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; sulfoxides such as dimethylsulfoxide and the like;amides such as N,N-dimethylformamide and the like; esters such as ethylacetate and the like; nitrites such as acetonitrile and the like; etc.These solvents may be used in admixture.

[0192] Moreover, the base which is used, if necessary, includes, forexample, organic and inorganic bases such as triethylamine,diisopropylethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU),pyridine, potassium tert-butoxide, sodium carbonate, potassiumcarbonate, sodium hydride and the like.

[0193] The halogenating agent includes, for example, phosphorusoxychloride, phosphorous oxybromide, phosphorus trichloride, phosphoruspentachloride, thionyl chloride and the like.

[0194] The sulfonylating agent includes, for example, methanesulfonylchloride, p-toluenesulfonyl chloride and the like.

[0195] The amount of the halogenating agent or sulfonylating agent usedand the amount of the base which is used, if necessary, are at leastequal to the molar amount of, preferably 1 to 5 moles per mole of, thecompound of the general formula [6] or its salt.

[0196] This reaction may be carried out at usually −10 to 100° C.,preferably 0 to 50° C., for 10 minutes to 24 hours.

[0197] The salt of the obtained compound of the general formula [11] orits salt may be used as it is without isolation in the subsequentreaction.

[0198] (3) Process for Producing Compound of the General Formula [4a] orits Salt

[0199] The compound of the general formula [4a] or its salt can beproduced by subjecting the compound of the general formula [11] or itssalt to ring-closing reaction in the presence of a base and in thepresence or absence of a catalyst.

[0200] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; aromatic hydrocarbons such as benzene, toluene and the like;ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethylether, di-n-butyl ether and the like; halogenated hydrocarbons such asmethylene chloride, chloroform and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide and thelike; sulfoxides such as dimethylsulfoxide and the like; water; etc.These solvents may be used in admixture.

[0201] The base which is used in this reaction includes, for example,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride and the like.

[0202] As the catalyst which is used, if necessary, there are used phasetransfer catalysts of usually known quaternary ammonium salts. However,preferably, there are mentioned tetra-n-butylammonium bromide,tetra-n-butylammonium hydrogensulfate and the like.

[0203] The amount of the base used is at least equal to the molar amountof, preferably 1 to 10 moles per mole of, the compound of the generalformula [11] or its salt, and the amount of the catalyst which is used,if necessary, is 0.01 to 0.2 mole per mole of the compound of thegeneral formula [11] or its salt.

[0204] This reaction may be carried out at usually 0 to 100° C.,preferably 0 to 40° C., for 10 minutes to 24 hours.

[0205] The compound of the general formula [4a] or its salt may be usedas it is without isolation in the subsequent reaction.

[0206] Furthermore, if necessary, after the removal of the protectinggroup of R⁵, a new protecting group may be introduced into the compoundof the general formula [4a] or its salt taking the subsequent productionroute into consideration.

[0207] When the compounds of the general formulas [4a], [6], [11] and[12] or their salts in the above-mentioned production process haveisomers (for example, optical isomers, geometrical isomers, tautomersand the like), these isomers can be used. Also, solvates, hydrates andcrystals of various forms can be used.

[0208] Moreover, when the compounds of the general formulas [4a], [6],[11] and [12] or their salts have an amino group, a hydroxyl group or acarboxyl group, it is possible to previously protect these groups with aconventional protecting group and remove the protecting group after thereaction in a manner known per se.

[0209] Next, a process for producing a compound of the general formula[1a] or its salt using the compound of the general formula [4a] or itssalt as the starting material is explained.

Production Process IIIB

[0210]

[0211] wherein R¹, R², R^(4a), R⁵, R⁶, R⁸, R⁹, A, X¹ and X² have thesame meanings as mentioned above.

[0212] (1) Process for Producing Compound of the General Formula [2b] orits Salt

[0213] The compound of the general formula [2b] or its salt can beproduced by subjecting the compound of the general formula [4a] or itssalt to borodation.

[0214] Specifically, it can be obtained by subjecting the compound ofthe general formula [4a] or its salt to lithiation or Grignard reactionaccording to, for example, the method described in Jikken Kagaku Koza,4th edition, Vol. 24, pages 61-90 (1992), and thereafter to reactionwith trialkyl borate.

[0215] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; ethers such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran, dioxane and the like; etc. These solvents may be usedin admixture.

[0216] The lithiating agent which is used in this reaction includes, forexample, alkyl metal or aryl metal reagents such as n-butyllithium,tert-butyllithium, phenyllithium, methyllithium and the like; and amidebases such as lithium diisopropylamide, lithium bistrimethylsilylamideand the like. Moreover, the Grignard reagent can be obtained by reactingmetallic magnesium with the compound represented by the formula [4a] orits salt.

[0217] The trialkyl borate which is used in this reaction includes, forexample, trimethyl borate, triethyl borate, triisopropyl borate,tributyl borate and the like.

[0218] The amounts of the lithiating agent, metallic magnesium andtrialkyl borate used are at least equal to the molar amount of,preferably 1 to 2 moles per mole of, the compound of the general formula[4a] or its salt.

[0219] This reaction may be carried out at usually −70 to 50° C.,preferably −60 to 0° C., for 10 minutes to 24 hours.

[0220] The obtained compound of the general formula [2b] or its salt maybe used as it is without isolation in the subsequent reaction.

[0221] (2) Process for Producing Compound of the General Formula [1a] orits Salt

[0222] The compound of the general formula [1a] or its salt can beobtained by subjecting the compound of the general formula [2b] or itssalt and the compound of the general formula [3] or its salt to couplingreaction using a palladium catalyst in the presence or absence of abase.

[0223] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andincludes, for example, water; alcohols such as methanol, ethanol,propanol and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as methylenechloride, chloroform, dichloroethane and the like; ethers such asdioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, ethylene glycol dimethyl ether and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxideand the like; etc. These solvents may be used in admixture.

[0224] The base which is used, if desired, in this reaction includes,for example, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, triethylamine and the like, and the amount of the base usedis at least equal to the molar amount of, preferably 2 to 5 moles permole of, the compound of the general formula [3] or its salt.

[0225] Moreover, the palladium catalyst which is used in this reactionincludes, for example, metallic palladium such as palladium-activatedcarbon, palladium black and the like; inorganic palladium salts such aspalladium chloride and the like; organic palladium salts such aspalladium acetate and the like; and organic palladium complexes such astetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and thelike.

[0226] The amount of the palladium catalyst used is at least 0.00001mole, preferably 0.001 to 0.05 mole, per mole of the compound of thegeneral formula [3] or its salt.

[0227] The amount of the compound of the general formula [2b] or itssalt used is at least equal to the molar amount of, preferably 1.0 to1.5 moles per mole of, the compound of the general formula [3] or itssalt.

[0228] This coupling reaction may be carried out usually in anatmosphere of an inert gas (for example, argon, nitrogen) at 50 to 170°C. for 1 minute to 24 hours.

[0229] The salts of the compounds of the general formulas [1a], [2b] and[3] in Production Process IIIB include the same salts as explainedabove.

[0230] The compound of the general formula [3] or its salt can beproduced by, for example, the method described in WO97/29102.

[0231] IV. Process for Producing 7-bromoquinolonecarboxylic AcidDerivative

Production Process IVA

[0232]

[0233] wherein R^(1b), R^(2a) and R^(7a) have the same meanings asmentioned above; R^(1a) represents a carboxyl-protecting group; and Xrepresents a halogen atom.

[0234] As the compounds of the general formulas [3a] and [13] to [19]can be converted to their salts, and as these salts, there can bementioned usually known salts at basic groups such as amino group andthe like and at acidic groups such as hydroxyl group, carboxyl group andthe like. The salts at the basic groups include, for example, salts withmineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acidand the like; salts with organic carboxylic acids such as tartaric acid,formic acid, lactic acid, citric acid, trichloroacetic acid,trifluoroacetic acid and the like; and salts with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid and the like. Also,the salts at the acidic groups include, for example, salts with alkalimetals such as sodium, potassium and the like; salts with alkaline earthmetals such as calcium, magnesium and the like; salts with ammonium;salts with nitrogen-containing organic bases such as trimethylamine,triethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine,procaine, dibenzylamine, N-benzyl-b-phenethylamine, 1-ephenamine,N,N′-dibenzylethylenediamine and the like; etc.

[0235] (1) Process for Producing Compound of the General Formula [15] orits Salt

[0236] The compound of the general formula [15] or its salt can beproduced by reacting a compound of the general formula [13] or its saltwith a compound of the general formula [14] in the presence or absenceof a base.

[0237] The solvent which is used in this reaction may be any solvent asfar as it does not adversely affect the reaction, and includes, forexample, aliphatic hydrocarbons such as n-hexane, cyclohexane and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such asmethylene chloride, chloroform, dichloroethane and the like; amides suchas N,N-dimethylformamide, N,N-dimethylacetamide and the like; nitritessuch as acetonitrile and the like; sulfoxides such as dimethylsulfoxideand the like; water; etc. These solvents may be used in admixture.Moreover, when water is used as the solvent, the use of a usually knownphase transfer catalyst is effective.

[0238] The phase transfer catalyst used includes, for example,quaternary ammonium salts such as tetramethylammonium bromide,tetrabutylammonium bromide, tetrabutylammonium chloride,tetrabutylammonium hydrogensulfate and the like. When the phase transfercatalyst is used, the amount thereof used is at least 0.1 mole,preferably 0.3 to 1.0 mole, per mole of the compound of the generalformula [13] or its salt.

[0239] As the base which is used, if desired, there are mentioned sodiumhydroxide, potassium hydroxide, sodium hydrogencarbonate, potassiumcarbonate, potassium tert-butoxide, sodium hydride and the like.

[0240] The amounts of the base and the compound of the general formula[14] used is each at least equal to the molar amount of, preferably 1 to10 moles per mole of, the compound of the general formula [13] or itssalt.

[0241] This reaction may be carried out usually at 0 to 180° C. for 5minutes to 30 hours.

[0242] The obtained compound of the general formula [15] or its salt maybe used as it is without isolation in the subsequent reaction.

[0243] (2) Process for Producing Compound of the General Formula [16] orits Salt

[0244] The compound of the general formula [16] or its salt can beobtained by subjecting the compound of the general formula [15] or itssalt to conventional elimination reaction of carboxyl-protecting group.

[0245] (3) Process for Producing Compound of the General Formula [17] orits Salt

[0246] The compound of the general formula [17] or its salt can beobtained by subjecting the compound of the general formula [16] or itssalt to ketoesterification reaction usually known in this field.

[0247] (3-a) The compound of the general formula [17] or its salt can beobtained by activating the carboxyl group of the compound of the generalformula [16] or its salt according to the method described in Angew.Chem. Int. Ed. Engl., Vol. 18, page 72 (1979), for example, byconverting the carboxyl group to an active acid amide form or the likeusing N,N′-carbonyldiimidazole, and thereafter reacting the activatedspecies with a magnesium salt of a malonic acid monoester.

[0248] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andincludes, for example, aromatic hydrocarbons such as benzene, toluene,xylene and the like; ethers such as dioxane, tetrahydrofuran, diethylether and the like; halogenated hydrocarbons such as methylene chloride,chloroform, dichloroethane and the like; and amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like. Thesesolvents may be used in admixture.

[0249] The amount of the magnesium salt of a malonic acid monoester usedis at least equal to the molar amount of, preferably 1 to 2 moles permole of, the compound of the general formula [16] or its salt.

[0250] This reaction may be carried out at usually 0 to 100° C.,preferably 10 to 80° C., for 5 minutes to 30 hours.

[0251] (3-b). Alternatively, the compound of the general formula [17] orits salt can be obtained by, for example, converting the carboxyl groupof the compound of the general formula [16] or its salt to an acidhalide using a halogenating agent such as thionyl chloride or the like,thereafter reacting the acid halide with a salt of a malonic aciddiester with a metal such as sodium, ethoxy-magnesium or the like, andthen subjecting the reaction product to partial removal of thecarboxyl-protecting group and decarbonization reaction usingp-toluenesulfonic acid or trifluoroacetic acid in a water-containingsolvent.

[0252] The solvent which is used in the reaction of the acid halide withthe metal salt of a malonic acid diester is not particularly limited asfar as it does not adversely affect the reaction, and specificallyincludes the same solvents as in (3-a) above.

[0253] The amount of the metal salt of a malonic acid diester used is atleast equal to the molar amount of, preferably 1 to 3 moles per mole of,the compound of the general formula [16] or its salt.

[0254] This reaction may be carried out usually at −50 to 100° C. for 5minutes to 30 hours.

[0255] (4) Process for Producing Compound of the General Formula [19] orits Salt

[0256] (4-a) The compound of the general formula [19] or its salt can beobtained by reacting the compound of the general formula [17] or itssalt with an orthoester such as methyl orthoformate, ethyl orthoformateor the like in acetic anhydride and thereafter reacting the reactionproduct with a compound of the general formula [18] or its salt.

[0257] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andinclude, for example, aromatic hydrocarbons such as benzene, toluene,xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole,diethylene glycol diethyl ether, methyl Cellosolve and the like;alcohols such as methanol, ethanol, propanol and the like; halogenatedhydrocarbons such as methylene chloride, chloroform, dichloroethane andthe like; amides such as N,N-dimethylformamide, N,N-dimethylacetamideand the like; sulfoxides such as dimethyl sulfoxide and the like; etc.These solvents may be used in admixture.

[0258] The amount of the orthoester used is at least equal to the molaramount of, preferably 1 to 10 moles per mole of, the compound of thegeneral formula [17] or its salt. These reactions may be carried out atusually 0 to 150° C., preferably 50 to 150° C., for 20 minutes to 50hours.

[0259] In order to subsequently react the compound of the generalformula [18] or its salt, it is sufficient to use this compound of thegeneral formula [18] or its salt in an amount at least equal to themolar amount of the compound of the general formula [17] or its salt andit is sufficient to carry out the reaction at usually 0 to 1000C,preferably 10 to 60° C., for 20 minutes to 30 hours.

[0260] (4-b) Alternatively, the compound of the general formula [19] orits salt can also be derived by reacting the compound of the generalformula [17] or its salt with an acetal such as N,N-dimethylformamidedimethyl acetal, N,N-dimethylformamide diethylacetal or the like in thepresence or absence of an acid anhydride such as acetic anhydride or thelike and thereafter reacting the reaction product with the compound ofthe general formula [18] or its salt.

[0261] When the acid anhydride is used, the amount thereof used is atleast equal to the molar amount of, preferably 1 to 5 moles per mole of,the compound of the general formula [17] or its salt.

[0262] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andspecifically includes the same solvents as in (4-a) above.

[0263] The amount of the acetal used is at least equal to the molaramount of, preferably about 1 to 5 moles per mole of, the compound ofthe general formula [17] or its salt.

[0264] These reactions may be carried out at usually 0 to 100° C.,preferably 20 to 85° C., for 20 minutes to 50 hours.

[0265] In order to subsequently react the compound of the generalformula [18] or its salt, it is sufficient to use this compound of thegeneral formula [18] or its salt in an amount at least equal to themolar amount of the compound of the general formula [17] or its salt andit is sufficient to carry out the reaction at usually 0 to 100° C.,preferably 10 to 60° C. for 20 minutes to 30 hours.

[0266] (5) Process for Producing Compound of the General Formula [3a] orits Salt

[0267] The compound of the general formula [3a] or its salt can beobtained by subjecting a compound of the general formula [19] or itssalt to ring-closing reaction in the presence or absence of a fluoridesalt or a base.

[0268] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andincludes, for example, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; ethers such as dioxane, anisole,diethylene glycol dimethyl ether, dimethyl Cellosolve and the like;sulfoxides such as dimethyl sulfoxide and the like; water; etc. Thesesolvents may be used in admixture.

[0269] The fluoride salt which is used, if desired, in this reactionincludes, for example, sodium fluoride, potassium fluoride and the like.

[0270] The base which is used, if desired, in this reaction includes,for example, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodiumhydride and the like.

[0271] The amounts of the fluoride salt and base used is each at leastequal to the molar amount of, preferably 1.0 to 3.0 moles per mole of,the compound of the general formula [19] or its salt. This reaction maybe carried out usually at 0 to 180° C. for 5 minutes to 30 hours.

[0272] The obtained compound of the general formula [3a] or its salt maybe used as it is without isolation in the subsequent reaction.

[0273] The thus obtained compound of the general formula [3a] or itssalt can be converted to the other compounds of the general formula [3a]or their salts by subjecting the former to protection reaction and/ordeprotection reaction.

[0274] When the salts of the compounds of the general formulas [3a] and[13] to [19] or their salts in the above-mentioned production processhave isomers (for example, optical isomers, geometrical isomers,tautomers and the like), these isomers can be used, and solvates,hydrates and crystals of various forms can also be used.

[0275] Furthermore, when the compounds of the general formulas [3a] and[13] to [19] or their salts have an amino group, a hydroxyl group or acarboxyl group, it is possible to previously protect these groups with aconventional protecting group and remove the protecting group after thereaction in a manner known per se.

[0276] Next, a process for producing a compound of the general formula[1b] or its salt using the compound of the general formula [3a] or itssalt as the starting material is explained.

Production Process IVB

[0277]

[0278] wherein R¹, R^(1b), R^(2a), R³, R⁴, R⁵, R^(7a), R⁸ and R⁹ havethe same meanings as mentioned above.

[0279] The compound of the general formula [1b] or its salt can beproduced by subjecting the compound of the general formula [2] or itssalt and the compound of the general formula [3a] or its salt tocoupling reaction using a palladium catalyst in the presence or absenceof a base.

[0280] The solvent which is used in this reaction is not particularlylimited as far as it does not adversely affect the reaction, andincludes, for example, water; alcohols such as methanol, ethanol,propanol and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as methylenechloride, chloroform, dichloroethane and the like; ethers such asdioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether,dimethyl Cellosolve and the like; esters such as ethyl acetate, butylacetate and the like; ketones such as acetone,,methyl ethyl ketone andthe like; nitrites such as acetonitrile and the like; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like; etc. These solvents may be usedin admixture.

[0281] The base which is used, if desired, in this reaction includes,for example, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, triethylamine and the like.

[0282] The palladium catalyst which is used in this reaction includes,for example, metallic palladiums such as palladium-activated carbon,palladium black and the like; inorganic palladium salts such aspalladium chloride and the like; organic palladium salts such aspalladium acetate and the like; and organic palladium complexes such astetrakis(triphenylphosphine)palladium(0),bis(triphenyl-phosphine)palladium(II) chloride,1,11-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and thelike.

[0283] The amount of the palladium catalyst used is at least 0.01% bymole, preferably 0.1 to 1.0% by mole, based on the amount of thecompound of the general formula [3a] or its salt.

[0284] The amount of the compound of the general formula [2] or its saltused is at least equal to the molar amount of, preferably 1.0 to 1.5moles per mole of, the compound of the general formula [3a] or its salt.

[0285] This coupling reaction may be carried out usually in anatmosphere of an inert gas (for example, argon, nitrogen) at 50 to 170°C. for 1 minute to 24 hours.

[0286] The salts of the compound of the general formula [1b] include thesame salts as the above-mentioned salts of the compounds of the generalformulas [3a] and [13] to [19].

[0287] The compound of the general formula [2] or its salt can beproduced by, for example, the method described in WO97/29102 and theabove Production Processes IB and IIA.

[0288] The salts of the compound of the general formula [2] include thesame salts as the above-mentioned salts of the compounds of the generalformulas [3a] and [13] to [19].

[0289] v. Salt of 7-isoindoline-3-quinolinecarboxylic acid, HydrateThereof and Composition Comprising the Same as Active Ingredient

[0290] In order to produce(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (T-3811) methanesulfonate, it is sufficient to produce the same bya usually known process for producing a salt of a compound.Specifically, T-3811 methanesulfonate can be obtained by suspending ordissolving T-3811 in, for example, an alcohol such as methanol, ethanolor the like; N,N-dimethylformamide; a methanol-ether mixed solvent; orthe like, adding methanesulfonic acid to the resulting suspension orsolution to react with T-3811.

[0291] Moreover, T-3811 methanesulfonate can also be produced bydehydrating T-3811 methanesulfonate monohydrate in a solvent, forexample, an alcohol such as methanol, ethanol or the like;N,N-dimethylformamide; a methanolether mixed solvent; or the like.

[0292] In order to produce T-3811 methanesulfonate monohydrate, it issufficient to produce the same by a usually known method for producing ahydrate of salt of a compound. Specifically, T-3811 methanesulfonatemonohydrate can be produced by, for example, suspending or dissolvingT-3811 in a water-containing alcohol such as water-containing ethanol,water-containing isopropanol or the like; water-containing acetonitrile;water-containing acetone; water-containing tetrahydrofuran;water-containing acetic acid; water-containing N,N-dimethylformamide;water; or the like, adding methanesulfonic acid to the resultingsuspension or solution to react with T-3811.

[0293] When T-3811 methanesulfonate or its monohydrate is used as anactive ingredient to prepare a composition thereof with an inactiveingredient, it is preferable to prepare a preparation composition inwhich the inactive ingredient is a carrier acceptable as preparation.

[0294] The carrier acceptable as preparation which is used in thisinvention includes specifically excipients such as lactose, corn starch,crystalline cellulose, mannitol, erythritol, sucrose and the like;disintegrators such as sodium carboxymethyl starch, calcium carmellose,sodium croscarmellose, hydroxypropyl cellulose of a low substitutiondegree, crospovidone and the like; binders such as hydroxypropylcellulose, povidone, methyl cellulose and the like; lubricants such asmagnesium stearate, calcium stearate, talc, light anhydrous silicic acidand the like; coating agents such as hydroxypropylmethyl cellulose,ethyl cellulose, polyvinyl alcohol, methacrylic acid copolymer,hydroxypropylmethyl cellulose acetate succinate and the like;plasticizers such as macrogol, glycerine triacetate, triethyl citrateand the like; coloring agents such as iron sesquioxide, yellow ironsesquioxide, food yellow No. 5, titanium oxide and the like; sweeteningagents such as sodium saccharate, aspartame, hydrogenated maltose starchand the like; viscosity improvers such as gelatine, sodium alginate andthe like; tonicity agents such as mannitol, glucose, xylitol and thelike; pH-adjusting agents such as methanesulfonic acid, sodium lactatesolution and the like; solvents such as water for injection and thelike; surface active agents such as polysorbate 80, sorbitan aliphaticacid ester, macrogol 400 and the like; ointment bases such as whitevaseline, polyethylene glycol, propylene glycol, cetanol and the like;etc.

[0295] Furthermore, the amount of the T-3811 methanesulfonate or itsmonohydrate contained in the composition is usually 0.05 to 70% byweight, preferably 0.5 to 20% by weight, based on the weight of thecomposition.

[0296] The composition of this invention can be prepared in variousdosage forms, for example, internal solid and liquid dosage forms suchas tablet, capsule, granule, pilule, grain, powder, syrup and the like;solutions such as injection, eye drop and the like; hemi-solid dosageforms such as ointment, cream, gel, jelly and the like.

[0297] The dosage regimen, dose and number of administrations of thecomposition of this invention can be appropriately selected dependingupon the symptom of patient, and it is usually sufficient to administerthe composition in a proportion of 0.1 to 100 mg/kg per day per adult interms of T-3811 in one to several portions.

[0298] Next, the solubility of various salts of T-3811 is explained.

Test Method

[0299] The solubility of each salt of T-3811 was determined by thefollowing method:

[0300] To about 50 mg of each salt of T-3811 is added 2 ml of distilledwater and they are stirred and mixed. This sample solution is exposed toultrasonic wave irradiation (SOLID STATE 1,200, Cho-onpa Kogyo) in coldwater for 3 hours and then filtered through a filter with a pore size of0.45-μm (MILLEX-HV13, MILLIPORE). The T-3811 content in this filtrate isdetermined by a liquid chromatography.

[0301] The results obtained are shown in Table 1. TABLE 1 SolubilitySalt of T-3811 pH (μg/ml) Methanesulfonate 3.66 16510 Phosphate 3.298520 L-lactate 4.40 1980 Sodium salt 10.11 2340 Citrate 3.90 420 Acetate4.22 6230 Hydrochloride 3.99 5450 Magnesium salt 7.58 60 Sulfate 3.461170

BEST MODE FOR CARRYING OUT THE INVENTION

[0302] Examples, Reference Examples, Production Examples and PreparationExamples are shown below to specifically explain this invention.However, this invention should not be construed to be limited thereto.

[0303] Incidentally, the mixing ratios in eluants are all by volume, andas the carriers in the column chromatography, there was used Silica Gel60 (70 to 230 mesh) (MERCK & CO., INC.) or BW-127ZH (manufactured byFuji Silicia Chemical Co., Ltd.).

[0304] Moreover, the abbreviation used has the following meaning:

[0305] TFA: Trifluoroacetic acid

EXAMPLE I-1

[0306] In 5 ml of toluene is dissolved 500 mg of(R)-5-bromo-2-(2,2-dimethylpropanoyl)-1-methyl-isoindoline, and theretoare added successively 510 mg of triethylamine, 35 mg ofbis(triphenylphosphine)palladium(II) chloride and 330 mg of4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Thereafter, the resultingmixture is heated under reflux for 5 hours in a nitrogen atmosphere.Subsequently, to the reaction mixture are added 480 mg of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,360 mg of sodium carbonate and 35 mg ofbis(triphenyl-phosphine)palladium(II) chloride and then the resultingmixture is heated under reflux for 3 hours in a nitrogen atmosphere. Thereaction mixture is added to a mixed solvent of 20 ml of ethyl acetateand 10 ml of water and the organic layer is separated. The organic layerseparated is washed with saturated saline and then dried over anhydrousmagnesium sulfate. The solvent is removed by distillation under reducedpressure and the residue obtained is purified by a silica gel columnchromatography (eluant; hexane : ethyl acetate=1:2) to obtain 470 mg ofethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-isoindolin-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

[0307] IR (KBr) cm⁻¹: 1730, 1610

[0308] NMR (CDCl₃) δ ( value: 0.85-1.45 (4H, m), 1.37(9H, s), 1.40(3H,d, J=6.0 Hz), 1.50(3H, t, J=7.0 Hz), 4.12(1H, m), 4.41(2H, q, J=7.0 Hz),4.95(1H, d, J=12.0 Hz), 5.08(1H, d, J=12.0 Hz), 5.50(1H, q, J=6.0 Hz),5.90(1H, t, J=76.0 Hz), 7.39(1H, d, J=8.0 Hz), 7.41(1H, d, J=8.0 Hz),7.49(1H, s), 7.54(1H, d, J=8.0 Hz), 8.45(1H, d, J=8.0 Hz), 8.69(1H, s)

EXAMPLE I-2

[0309] In 10 ml of dioxane is dissolved 1 g of(R)-5-bromo-2-(2,2-dimethylpropanoyl)-1-methyl-isoindoline and theretoare added successively 1.02 g of triethylamine,1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 650 mg of4,4,5,5-tetramethyl-1,3,2-dioxoborolane, after which the resultingmixture is heated under reflux for 2 hours in an nitrogen atmosphere.The reaction mixture is added to a mixed solvent of 30 ml of ethylacetate and 20 ml of water and the pH is adjusted to 2 with 2moles/liter hydrochloric acid, after which the organic layer isseparated. The organic layer separated is washed with saturated salineand then dried over anhydrous magnesium sulfate. The solvent is removedby distillation under reduced pressure, and the residue obtained ispurified by a silica gel column chromatography (eluant; hexane:ethylacetate=5:1) to obtain 400 mg of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)isoindoline.

[0310] IR (KBr) cm⁻¹: 1740, 1620, 1360, 1145

[0311] NMR (CDCl₃) δ value: 1.33(9H, s), 1.35(12H, s), 1.46(3H, d, J=6.0Hz), 4.93(1H, d, J=12.0 Hz), 5.00(1H, d, J=12.0 Hz), 5.46(1H, q, J=6.0Hz), 7.25(1H, d, J=7.0 Hz), 7.71(1H, s), 7.75(1H, d, J=7.0 Hz)

EXAMPLE I-3

[0312] In 3 ml of dimethyl sulfoxide is dissolved 200 mg of(R)-5-bromo-2-(2,2-dimethylpropanoyl)-1-methylisoindoline and theretoare added successively 200 mg of potassium acetate, 14 mg ofbis(triphenylphosphine)-palladium(II) chloride and 170 mg of4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolane,after which the resulting mixture is heated under reflux for 5 hours ina nitrogen atmosphere. The reaction mixture is added to a mixed solventof 10 ml of ethyl acetate and 10 ml of water and then the pH is adjustedto 2 with 2 moles/liter hydrochloric acid, after which the organic layeris separated. The organic layer separated is washed with saturatedsaline and then dried over anhydrous magnesium sulfate. The solvent isremoved by distillation under reduced pressure and the residue obtainedis purified by a silica gel column chromatography (eluant; hexane :ethyl acetate=5:1) to obtain 140 mg of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)isoindoline.

EXAMPLE I-4

[0313] In 15 ml of ethanol is dissolved 2.5 g of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolineand thereto are added 2.8 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylateand 1.1 g of sodium carbonate. Subsequently, 150 mg of 10%palladium-activated carbon is added thereto under a nitrogen atmosphereand then heated under reflux for 3 hours in the same atmosphere. Aftercooling the reaction mixture, a mixed solvent of 15 ml of water and 30ml of acetone is added thereto, and the deposited crystals are collectedby filtration to obtain 3.6 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-isoindolin-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

Reference Example I-1

[0314] In 68 ml of conc. hydrochloric acid is suspended 34 g of ethyl1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-isoindolin-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate,and the suspension is heated under reflux for 3 hours, after which 340ml of water is added thereto and then 170 ml of the solvent is removedby distillation under atmospheric pressure over 3 hours. After coolingthe reaction mixture, 17 ml of ethanol is added thereto and the crystalsdeposited are collected by filtration. The resulting(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride is suspended in 340 ml of water, and the suspensionis adjusted to pH 7.5 with 2 moles/liter sodium hydroxide solution withcooling, after which the crystals deposited are collected by filtrationto obtain 25.55 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinoline-carboxylicacid monohydrate.

Reference Example I-2

[0315] In 192 ml of 50% ethanol is suspended 24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinoline-carboxylicacid monohydrate and the suspension is warmed to 40° C., after which5.71 g of methanesulfonic acid is added thereto to form a uniformsolution. Subsequently, 2.4 g of activated carbon is added to thesolution and the resulting mixture is stirred at the same temperaturefor 10 minutes and thereafter filtered. The filtrate is concentrated andthe deposited crystals are collected by filtration to obtain 26.64 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.

Reference Example II-1

[0316] In 1,300 ml of water is dissolved 130 g of sodium hydroxide andin the solution is suspended 188 g of (1R)-1-phenylethylamine, afterwhich 287 ml of pivaloyl chloride is dropwise added to the suspension at20° C. over 40 minutes. The resulting mixture is stirred at the sametemperature for 1.5 hours and the crystals deposited are collected byfiltration to obtain 289 g ofN-[(1R)-1-phenylethyl]-2,2-dimethylpropanamide.

[0317] [α]_(D)=97 (29° C., c=1.0, CHCl₃)

[0318] IR (KBr) cm⁻¹: ν_(c=o) 1637

[0319] NMR (CDCl₃) δ value: 1.20(9H,s), 1.48(3H, d, J=6.8 Hz), 5.11(1H,m), 5.8(1H, brs), 7.31(5H, s)

EXAMPLE II-1

[0320] In 466 ml of tetrahydrofuran is dissolved 77.7 g ofN-[(1R)-1-phenylethyl]-2,2-dimethylpropanamide and to this solution isdropwise added 500 ml of a n-hexane solution of n-butyllithium (1.6 Msolution) at −30° C. over 30 minutes. After the dropwise addition, thetemperature of the resulting mixture is elevated to 0° C. and themixture is stirred at the same temperature for 1.5 hours and then cooledagain to −30° C., after which carbon dioxide is introduced into themixture. After the introduction, the reaction mixture is added to amixed solvent of 500 ml of ethyl acetate and 932 ml of water and theaqueous layer is separated. To the aqueous layer is added 200 ml ofmethylene chloride, and then the resulting aqueous layer is adjusted topH 3 with 6 N hydrochloric acid and then the organic layer is separated.The solvent is removed from the organic layer by distillation underreduced pressure and the residue thus obtained is dissolved in 310 ml ofmethanol. To this solution is added 72.6 g of methanesulfonic acid andthe resulting mixture is heated under reflux for 3 hours and then cooledto 40° C., after which 777 ml of water is dropwise added to theresulting mixture and the crystals deposited are collected by filtrationto obtain 77.2 g of colorless crystals of methyl2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate.

[0321] [α]_(D)=52 (29° C., c=1.0, CHCl₃)

[0322] IR (KBr) cm⁻¹: ν_(c=o) 1722, 1639

[0323] NMR (CDCl₃) δ value: 1.17(9H, s), 1.47(3H, d, J=7.1 Hz), 3.93(3H,s), 5.4-5.6(1H, m), 7.1-7.6(4H, m), 7.86 (1H, dd, J=7.1, 1.2 Hz)

EXAMPLE II-2

[0324] In 560 ml of sulfuric acid is dissolved 70 g of methyl2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-benzoate and to thissolution is added 64.2 g of sodium N-bromoisocyanurate at 0° C., afterwhich the resulting mixture is stirred with ice-cooling for 3 hours. Thereaction mixture is added to a mixed solvent of 420 ml of methylenechloride and 1,050 ml of water and the insolubles are removed byfiltration and then the organic layer is separated. The organic layerobtained is washed with 0.5 N aqueous sodium hydroxide solution and thendried over anhydrous magnesium sulfate, after which the solvent isremoved by distillation under reduced pressure. The residue thusobtained is recrystallized from cyclohexane to obtain 74.2 g ofcolorless crystals of methyl5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate.

[0325] [α]_(D)=53 (29° C., c=1.0, CHCl₃)

[0326] IR (KBr) cm⁻¹: ν_(c=o) 1726, 1709, 1637

[0327] NMR (CDCl₃) δ value: 1.16(9H, s), 1.45(3H, d, J=7.1 Hz), 3.93(3H,s), 5.3-5.7(1H, m) 6.8-7.0(1H, m), 7.28(1H, d, J=8.3 Hz), 7.59(1H, dd,J=8.3, 2.2 Hz), 8.00(1H, d, J=2.2 Hz)

EXAMPLE II-3

[0328] In 420 ml of ethanol are suspended with ice-cooling 13.4 g ofsodium borohydride and 70.0 g of methyl5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-benzoate and tothe suspension is added 19.6 g of calcium chloride at 0° C., after whichthe resulting mixture is stirred with ice-cooling for 4 hours. Thereaction mixture is dropwise added to 359 ml of 1 N hydrochloric acidand then 840 ml of methylene chloride and 231 ml of water are addedthereto, after which the organic layer is separated. The organic layerobtained is washed with water and then dried over anhydrous magnesiumsulfate, after which the solvent is removed by distillation underreduced pressure. The residue obtained is dissolved 250 ml of diethyleneglycol dimethyl ether and thereto is added 32.4 ml of triethylamine,after which 16.7 ml of methanesulfonyl chloride is dropwise addedthereto with ice-cooling over 30 minutes. The resulting mixture isfurther stirred with ice-cooling for 30 minutes. The reaction mixture isdropwise added to 1,120 ml of water and the crystals deposited arecollected by filtration to obtain 70 g of colorless crystals of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino ethyl}benzylmethanesulfonate.

[0329] [α]_(D)=26 (26° C., c=1.0, CHCl₃)

[0330] IR (KBr) cm⁻¹: ν_(c=o) 1646

[0331] NMR (CDCl₃) δ value: 1.16(9H, s), 1.47(3H, d, J=6.8 Hz), 3.04(3H,s), 5.0-5.3(1H, m), 5.22(1H, d, J=11.8 Hz), 5.60(1H, d, J=11.8 Hz),5.8-6.0(1H, m), 7.20(1H, d, J=9.0 Hz), 7.5-7.6(2H, m)

EXAMPLE II-4

[0332] In 200 ml of diethylene glycol dimethyl ether is dissolved 25 gof 5-bromo-2-{(1R)-1-[(2,2-dimethyl- propanoyl)amino]ethyl}benzylmethanesulfonate and to this solution is added 6.73 g of sodiumtert-butoxide at 0° C., after which the resulting mixture is stirred at5° C. for 2 hours. To the reaction mixture is dropwise added 150 ml ofwater and the crystals deposited are collected by filtration, to obtain16.9 g of colorless crystals of1-[(1R)-5-bromo-1-methyl-2,3-dihydro-1H-2-isoindolyl]-2,2-dimethyl-1-propanone.

[0333] [α]_(D)=3 (29° C., c=1.0, CHCl₃)

[0334] IR (KBr) cm⁻¹: ν_(c=o) 1616

[0335] NMR (CDCl₃) δ value: 1.32(9H, s), 1.44(3H, d, J=6.4 Hz), 4.83(1H,d, J=14.5 Hz), 5.04(1H, d, J=14.5 Hz), 5.38 (1H, q, J=6.4 Hz),7.0-7.5(3H, m)

EXAMPLE II-5

[0336] In 130 ml of 6 moles/liter hydrochloric acid, 16.5 g of1-[(1R)-5-bromo-1-methyl-2,3-dihydro-1H-2-isoinodolyl]-2,2-dimethyl-1-propanoneis heated under reflux for 5 hours. The reaction mixture is cooled toroom temperature, then washed with toluene and thereafter neutralizedwith 5 moles/liter aqueous sodium hydroxide solution, after which themixture is subjected to extraction with 81 ml of methylene chloride. Theextract is dried over anhydrous magnesium sulfate and thereto are added8 ml of triethylamine and then 15.25 g of trityl chloride, after whichthe resulting mixture is stirred at room temperature for 1 hour. Thereaction mixture is washed with water and then the solvent is removed bydistillation under reduced pressure, after which the residue thusobtained is recrystallized from isopropyl alcohol to obtain 16.7 g ofpale violet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole.

[0337] [α]_(D)=92 (29° C. c=1.0, CHCl₃)

[0338] IR (KBr) cm⁻¹: ν_(c=o) 1596

[0339] NMR (CDCl₃) δ value: 1.37(3H, d, J=6.4 Hz), 3.99(1H, d, J=16.8Hz), 4.3-4.6(2H, m), 6.5-7.6(18H, m)

EXAMPLE II-6

[0340] In 100 ml of toluene is dissolved 10.0 g of methyl5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-ethyl}benzoate, and tothe solution is added 3.1 g of sodium tert-butoxide, after which theresulting mixture is stirred with ice-cooling for 15 minutes. Thereaction mixture is added to a mixed solvent of 150 ml of water and 100ml of ethyl acetate and the resulting mixture is neutralized with 2 Nhydrochloric acid, after which the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, after which the solvent is removed bydistillation under reduced pressure. The residue thus obtained isrecrystallized from isopropyl alcohol to obtain 5.7 g of colorlesscrystals of (3R)-6-bromo-3-methyl-2,3-dihydro-1H-1-isoindolone.

[0341] [α]_(D)=17.7 (29° C., c=1.0, CHCl₃)

[0342] IR (KBr) cm⁻¹: ν_(c=o) 1702, 1655

[0343] NMR (CDCl₃) δ value: 1.51(3H, d, J=6.8 Hz), 4.68(1H, q, J=6.8Hz), 7.31(1H, d, J=7.8 Hz), 7.69(1H, dd, J=7.8, 1.7 Hz), 7.95(1H, d,J=1.7 Hz)

EXAMPLE II-7

[0344] In 1,200 ml of tetrahydrofuran are suspended with ice-cooling60.3 g of sodium borohydride and 40.0 g of(3R)-6-bromo-3-methyl-2,3-dihydro-1H-1-isoindolone, and to the resultingsuspension is added 301 g of boron trifluoride-diethyl ether complex at0° C., after which the resulting mixture is heated under reflux for 3hours. The reaction mixture is cooled and then added to a mixed solventof 2,000 ml of water and 700 ml of methylene chloride and the pH isadjusted to 10 with a 5 moles/liter aqueous sodium hydroxide solution,after which the organic layer is separated. The organic layer obtainedis washed with water and the solvent is removed by distillation underreduced pressure, after which the residue obtained is dissolved in 200ml of 6 moles/liter hydrochloric acid. To the solution is added 100 mlof toluene and the resulting mixture is heated under reflux for 5minutes. The reaction mixture is cooled and thereafter the aqueous layeris adjusted to pH 10 with 5 N aqueous sodium hydroxide solution and thensubjected to extraction with 200 ml of methylene chloride. The extractis dried over anhydrous magnesium sulfate and then the solvent isremoved by distillation under reduced pressure to obtain 30 g of a redoily product of (1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole.

[0345] NMR (CDCl₃) δ value: 1.41(3H, d, J=6.3 Hz), 2.27(1H, s),3.8-4.6(3H, m), 7.0-7.6(3H, m)

EXAMPLE II-8

[0346] In 120 ml of ethanol is dissolved 30 g of(1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole, and 12 ml of conc.hydrochloric acid is added to the solution, after which the solvent isremoved by distillation under reduced pressure. The residue thusobtained is recrystallized from isopropyl alcohol to obtain 27.7 g ofred crystals of (1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindolehydrochloride.

[0347] [α]_(D)=12.8 (27° C., c=1.00, CHCl₃)

[0348] IR (KBr) cm⁻¹: 1602, 1593

EXAMPLE II-9

[0349] In 32 ml of methylene chloride is suspended 3.2 g of(1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole hydrochloride and to thesuspension is added 3.94 ml of triethylamine, after which a solution of3.95 g of trityl chloride in 10 ml of methylene chloride is addedthereto and the resulting mixture is stirred at room temperature for 2hours. The reaction mixture is washed with water and then the solvent isremoved by distillation under reduced pressure, after which the residuethus obtained is recrystallized from isopropyl alcohol to obtain 4.83 gof pale violet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole. The physicalproperty values of this compound were identical with those of thecompound obtained in Examples II-5.

EXAMPLE II-10

[0350] In 67.5 ml of tetrahydrofuran is dissolved 13.5 g of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole and to thissolution is dropwise added 19.7 ml of an n-hexane solution ofn-butyllithium (1.66 M solution) at −50° C. over 10 minutes. At the sametemperature, the resulting mixture is stirred for 45 minutes andthereafter 5.87 g of triisopropyl borate is dropwise added thereto over15 minutes, after which the resulting mixture is further stirred at thesame temperature for 1 hour. The reaction mixture is added to 67.5 ml ofwater and the resulting mixture is stirred at 10° C. for 1 hour and thenadjusted to pH 7 with acetic acid, after which the organic layer isseparated and dried over anhydrous magnesium sulfate. Thereafter, thesolvent is removed from the dried layer by distillation under reducedpressure. The residue thus obtained is recrystallized from cyclohexaneto obtain 8.6 g of brownish gray crystals of(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronic acid.

[0351] [α]_(D)=59 (28° C., c=1.0, CHCl₃)

[0352] IR (KBr) cm⁻¹: ν_(B-O) 1356

[0353] NMR (CDCl₃) δ value: 1.40(3H, d, J=6.3 Hz), 4.1-4.8 (3H, m),6.6-7.8(18H, m)

EXAMPLE II-11

[0354] In a mixed solvent of 4 ml of tetrahydrofuran and 1.5 ml ofhexane is suspended 1 g of(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronic acid and then0.24 g of diethanolamine is added to the suspension, after which theresulting mixture is stirred for 20 minutes. The crystals deposited arecollected by filtration to obtain 0.88 g of colorless crystals of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane.

[0355] [α]_(D)=57.2 (25° C., c=0.33, CHCl₃)

[0356] IR (KBr) cm⁻¹: 1490, 1446

[0357] NMR (CDCl₃) δ value: 1.18(3H, d, J=6.1 Hz), 2.4-4.6 (12H, m),6.5-7.8 (18H, m)

Production Example II-1

[0358] In a mixed solvent of 2 ml of water and 5 ml of ethyl acetate issuspended 1.34 g of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocaneand to this suspension are added 1.0 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,0.55 g of sodium carbonate and 0.05 g ofbis(triphenylphosphine)palladium(II) chloride, after which the resultingmixture is heated under reflux for 3 hours in a nitrogen atmosphere. Thereaction mixture is added to a mixed solvent of 10 ml of methylenechloride and 10 ml of water, and the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, after which the solvent is removed bydistillation under reduced pressure. The residue thus obtained isrecrystallized from ethanol to obtain 1.55 g of ethyl1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

[0359] [α]_(D)=32 (27° C., c=1.0, CHCl₃)

[0360] IR (KBr) cm⁻¹: ν_(c=o) 1734, 1690

[0361] NMR (CDCl₃) δ value: 0.8-1.9(10H, m), 3.9-4.9(6H, m), 5.51(1H, t,J=75 Hz), 6.7-8.0(19H, m), 8.35(1H, d, J=8.0 Hz), 8.66(1H, s)

Production Example II-2

[0362] In a mixed solvent of 50.6 ml of water and 50.6 ml of diethyleneglycol dimethyl ether is suspended 13.5 g of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocaneand to this suspension is added 1.58 ml of acetic acid, after which theresulting mixture is stirred for 30 minutes. To this mixture are furtheradded 10.1 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,5.59 g of sodium carbonate and 0.088 g ofbis(triphenylphosphine)-palladium(II) chloride, and the resultingmixture is heated under reflux for 2 hours in a nitrogen atmosphere. Thereaction mixture is cooled to 40° C. and thereafter the organic layer isseparated. To the organic layer obtained is added 30 ml of ethanol andthe crystals deposited are collected by filtration to obtain 17.3 g ofethyl1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.The physical property values of this compound were identical with thoseof the compound obtained in Production Example II-1.

EXAMPLE III-1

[0363] In 495 ml of water is dissolved 83.7 g of sodium hydroxide and tothis solution are added 165 g of R-(+)-1-(4-bromophenyl)ethylaminehydrochloride and 495 ml of isopropanol, after which 92.5 g of pivaloylchloride is dropwise added to the resulting solution at 20° C. over 1.5hours. At the same temperature, the resulting mixture is stirred for 30minutes, and thereafter, 660 ml of water is dropwise added to themixture over 30 minutes, after which the resulting mixture is cooled to10° C. The mixture is stirred at the same temperature for 1 hour andthereafter the deposits are collected by filtration to obtain 193.5 g(yield: 97.6%) of colorless crystals ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide.

[0364] Melting point: 132-134° C.

[0365] [α]_(D)+92° (25° C., c=1.0, CHCl₃)

[0366] IR (KBr) cm⁻¹: ν_(c=o) 1636

[0367] NMR (CDCl₃) δ value: 1.19(9H, s), 1.45(3H, d, J=6.8 Hz),4.90-5.20(1H, m), 5.70-6.00(1H, m), 7.16(2H, d, J=8.5 Hz), 7.45(2H, d,J=8.5 Hz)

EXAMPLE III-2

[0368] In 10 ml of tetrahydrofuran is dissolved 2 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 14.3 ml of phenyllithium (1.48 Mcyclohexane-diethyl ether solution), after which the temperature of theresulting mixture is elevated to −5° C. and the mixture is stirred atthe same temperature for 4 hours. Subsequently, 1.06 g ofparaformaldehyde is added thereto and the mixture is stirred at 5° C.for 1 hour, after which 6 ml of water is added to the reaction mixtureand the organic layer is separated. The organic layer obtained is driedover anhydrous magnesium sulfate and the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bysilica gel chromatography (eluant; n-hexane:ethyl acetate=2:1) to obtain1.48 g (yield: 66.9%) of5-bromo-2-{(1R)-1-[(2.2-dimethylpropanoyl)amino]-ethyl}benzyl alcohol.

[0369] IR (KBr) cm⁻¹: ν_(c=o) 1639, 1610

[0370] NMR (CDCl₃) δ value: 1.14(9H, s), 1.46(3H, d, J=6.8 Hz),4.3-5.4(4H, m), 6.0-6.4(1H, m), 7.0-7.6(3H, m)

EXAMPLE III-3

[0371] In 135 ml of methylene chloride is dissolved 13.50 g of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)-amino]ethyl}benzyl alcohol,and to this solution are added with ice-cooling 6.59 ml of triethylamineand 3.66 ml of methanesulfonyl chloride, after which the resultingmixture is stirred with ice-cooling for 1 hour. Subsequently, 50 ml ofwater is added to the reaction mixture and the pH is adjusted to 2.0with 2 moles/liter hydrochloric acid and thereafter the organic layer isseparated. The organic layer obtained is washed with water and thendried over anhydrous magnesium sulfate, after which the solvent isremoved by distillation under reduced pressure. To the residue obtainedare added 50 ml of toluene and 50 ml of cyclohexane, and the depositsare collected by filtration to obtain 11.5 g (yield: 68.2%) of colorlesscrystals of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-benzylmethanesulfonate.

[0372] [α]_(D)+260 (25° C., c=1.0, CHCl₃)

[0373] IR (KBr) cm⁻¹: ν_(c=o) 1646

[0374] NMR (CDCl₃) δ value: 1.16(9H, s), 1.47(3H, d, J=6.8 Hz), 3.04(3H,s), 5.0-5.3(1H, m), 5.22(1H, d, J=11.8 Hz), 5.60(1H, d, J=11.8 Hz),5.8-6.0(1H, m), 7.20(1H, d, J=9.0 Hz), 7.5-7.6(2H, m)

EXAMPLE III-4

[0375] In 225 ml of tetrahydrofuran is dissolved 45 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 505 ml of phenyllithium (0.94 Mcyclohexane-diethyl ether solution) at −30° C., after which thetemperature of the mixture is elevated to −5° C. and the mixture isstirred at the same temperature for 3 hours. Subsequently, 23.77 g ofparaformaldehyde is added to the mixture and the resulting mixture isstirred at 5° C. for 1 hour, after which 180 ml of water is added to thereaction mixture and the organic layer is separated. The organic layerobtained is washed with saturated saline and then dried over Zeolum 4A(manufactured by TOSOH CORP.), after which Zeolum 4A is removed byfiltration. To the filtrate obtained is added 43.26 g of triethylamineand the resulting mixture is cooled to 10° C., after which 31.07 g ofacetyl chloride is dropwise added to the mixture over 30 minutes. Theresulting mixture is stirred at the same temperature for 25 minutes.Subsequently, 180 ml of water is added to the reaction mixture and thenthe pH is adjusted to 2.0 with 2 moles/liter hydrochloric acid, afterwhich the organic layer is separated. The organic layer obtained iswashed successively with 5% (w/w) sodium hydrogencarbonate and water,and thereafter, the solvent is removed by distillation under atmosphericpressure. To the residue obtained are added 113 ml of cyclohexane and135 ml of n-hexane and the deposits are collected by filtration toobtain 33.93 g (yield: 60.1%) of colorless crystals of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-benzyl acetate.

[0376] Melting point: 109-112.5° C.

[0377] IR (KBr) cm⁻¹: ν_(c=o) 1750, 1734, 1635

[0378] NMR (CDCl₃) δ value: 1.17(9H, s), 1.45(3H, d, J=6.8 Hz), 2.10(3H,s), 4.90-5.50(3H, m), 5.70-6.10(1H, m), 7.10-7.60(3H, m)

EXAMPLE III-5

[0379] In 20 ml of tetrahydrofuran is dissolved 4.0 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 45 ml of phenyllithium (0.94 Mcyclohexane-diethyl ether solution) at −30° C., after which thetemperature of the resulting mixture is elevated to −5° C. and themixture is stirred at the same temperature for 2 hours. Subsequently,1.69 g of paraformaldehyde is added to the mixture and the resultingmixture is stirred at 5° C. for 1 hour, after which 160 ml of water isadded to the reaction mixture and the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedwith Zeolum 4A, after which Zeolum 4A is removed from the layer byfiltration. The filtrate obtained is cooled to −15° C. and then 2.10 mlof thionyl chloride is added to the filtrate, after which thetemperature of the resulting mixture is elevated to room temperature andthe mixture is stirred at the same temperature for 1 hour. Subsequently,8 ml of water is added to the reaction mixture and the pH is adjusted to5.5 with 5 moles/liter sodium hydroxide solution, after which theorganic layer is separated. The organic layer obtained is subjected toremoval of the solvent by distillation under atmospheric pressure and tothe residue obtained are added 12 ml of cyclohexane and 12 ml ofn-hexane and then the deposits are collected by filtration to obtain2.43 g (yield 52.0%) of colorless crystals of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl chloride.

[0380] IR (KBr) cm⁻¹: ν_(c=o) 1634

[0381] NMR (CDCl₃) δ value: 1.16(9H, s), 1.49(3H, d, J=6.8 Hz), 4.48(1H,d, J=11.7 Hz), 5.07(1H, d, J=11.7 Hz), 5.00-5.40(1H, m), 5.70-6.10(1H,m), 7.10-7.60(3H, m)

EXAMPLE III-6

[0382] To a mixed solution of 30 g of a 50% (w/w) aqueous sodiumhydroxide solution and 40 ml of toluene are added 10 g of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)-amino]ethyl}benzyl acetateand 0.27 g of tetra-n-butylammonium bromide at room temperature, and thetemperature of the resulting mixture is elevated to 35° C., after whichthe mixture is stirred for 1 hour. The mixture is cooled to roomtemperature and thereafter 30 ml of water is added to the reactionmixture, after which the organic layer is separated. The organic layeris dried over anhydrous magnesium sulfate and then the anhydrousmagnesium sulfate is removed by filtration. To the filtrate obtained isadded 3.98 g of triethylamine and the resulting mixture is cooled to 10°C., after which 3.86 g of methanesulfonyl chloride is dropwise addedthereto over 10 minutes. At the same temperature, the mixture is stirredfor 30 minutes and thereafter 30 ml of water is added to the reactionmixture, after which the organic layer is separated. To the organiclayer obtained is added 30 g of a 50% (w/w) aqueous sodium hydroxidesolution and the temperature of the resulting mixture is elevated to 35°C., after which 0.27 g of tetra-n-butylammonium bromide is addedthereto. The mixture is stirred at the same temperature for 1 hour and35 minutes and then cooled to room temperature, after which 30 ml ofwater is added to the reaction mixture and the organic layer isseparated. The organic layer separated is washed with water andthereafter the solvent is removed by distillation under reducedpressure, after which to the residue obtained are added 10 ml ofethylene glycol and 20 ml of conc. hydrochloric acid. The resultingmixture is heated under reflux for 4 hours. After cooling, to thereaction mixture are added 40 ml of water and 20 ml of toluene and thenthe aqueous layer is separated. The aqueous layer obtained is treatedwith active carbon and thereto is then added 40 ml of methylenechloride, after which the pH is adjusted to 11 with 20% (w/w) aqueoussodium hydroxide solution. Subsequently, the organic layer is separatedand dried over anhydrous magnesium sulfate and thereafter to the organiclayer is added 2.98 g of triethylamine, after which the resultingmixture is cooled to −15° C. and then 7.43 g of trityl chloride is addedthereto. The temperature of the reaction mixture is elevated to roomtemperature and the mixture is stirred at room temperature for 30minutes, after which 20 ml of water is added thereto and the organiclayer is separated. The organic layer separated is subjected to removalof the solvent by distillation under atmospheric pressure and 45 ml ofisopropanol is added to the residue obtained, after which the depositswere collected by filtration to obtain 10.11 g (yield: 79.0%) of paleviolet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole.

[0383] [α]_(D)+92° (25° C., c=1.0, CHCl₃)

[0384] IR (KBr) cm⁻¹: 1596

[0385] NMR (CDCl₃) δ value: 1.37(3H, d, J=6.4 Hz), 3.99(1H, d, J=16.8Hz), 4.3-4.6(2H, m), 6.5-7.6(18H, m)

EXAMPLE III-7

[0386] The same ring-closing reaction as in Example III-6 is repeated byreplacing the5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl acetate by5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl chloride toobtain (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole.

EXAMPLE III-8

[0387] In 230 ml of tetrahydrofuran is dissolved 46 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 300 ml of phenyllithium (1.62 Mcyclohexane-diethyl ether solution) at −35° C. and the temperature ofthe resulting mixture is elevated to −5° C., after which the mixture isstirred at the same temperature for 2 hours. Subsequently, 19.46 g ofparaformaldehyde is added to the mixture and the resulting mixture isstirred at 5° C. for 1 hour, after which 138 ml of water is added to thereaction mixture, and the organic layer is separated. The organic layerobtained is dried with Zeolum 4A and then Zeolum 4A is removed byfiltration. To the filtrate obtained are added 40.95 g of triethylamineand 37.10 g of methanesulfonyl chloride at 10° C. and the resultingmixture is stirred at the same temperature for 30 minutes. Subsequently,92 ml of water is added to the reaction mixture and the pH is adjustedto 2.5 with 6 moles/liter hydrochloric acid, after which the organiclayer is separated. To the organic layer separated are added 138 g of50% (w/w) aqueous sodium hydroxide solution and 4.6 g oftetra-n-butylammonium bromide and the resulting mixture is stirred at20° C. for 2 hours, after which 92 ml of water is added to the reactionmixture and the organic layer is separated. To the organic layerobtained is added 92 ml of water and the pH is adjusted to 3.0 with 6moles/liter hydrochloric acid, after which the solvent is removed bydistillation under atmospheric pressure. To the residue obtained areadded 46 ml of ethylene glycol and 92 ml of conc. hydrochloric acid, andthe resulting mixture is heated under reflux for 6 hours. After cooling,to the reaction mixture are added 138 ml of water and 92 ml of toluene,and the aqueous layer is separated. The aqueous layer is treated withactive carbon and thereafter 138 ml of methylene chloride is addedthereto, after which the pH is adjusted to 11 with 5 moles/liter aqueoussodium hydroxide solution. Subsequently, the organic layer is separatedand dried over Zeolum 4A. To the organic layer obtained is added 13.10 gof triethylamine and the result- ing mixture is cooled to −15° C. andthen 31.59 g of trityl chloride is added thereto. The temperature of thereaction mixture is elevated to room temperature and the mixture isstirred at room temperature for 30 minutes, after which 138 ml of wateris added thereto and the organic layer is separated. The organic layerseparated is subjected to removal of the solvent by distillation underatmospheric pressure and to the residue obtained is added 207 ml ofisopropanol and the deposits are collected by filtration to obtain 42.5g (yield: 57.7%) of pale violet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole. The physicalproperty values of this compound were identical with those of thecompound obtained in Example III-6.

Production Example III-1

[0388] In 67.5 ml of tetrahydrofuran is dissolved 13.5 g of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole, and to thissolution is dropwise added 19.7 ml of an n-hexane solution ofn-butyllithium (1.66 M solution) at −50° C. over 10 minutes. At the sametemperature, the resulting mixture is stirred for 45 minutes andthereafter 5.87 g of triisopropyl borate is dropwise added to themixture over 15 minutes, after which the mixture is stirred at the sametemperature for 1 hour. The reaction mixture is added to 67.5 ml ofwater and the resulting mixture is stirred at 10° C. for 1 hour, afterwhich the pH is adjusted to 7 with acetic acid and the organic layer isseparated. The organic layer separated is dried over anhydrous magnesiumsulfate and thereafter the solvent is removed from the layer bydistillation under reduced pressure. The residue obtained isrecrystallized from cyclohexane to obtain 8.6 g of brownish graycrystals of (1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronicacid.

[0389] [α]_(D)+59° (28° C., c=1.0, CHCl₃)

[0390] IR (KBr) cm⁻¹: ν_(B-O) 1356

[0391] NMR (CDCl₃) δ value: 1.40(3H, d, J=6.3 Hz), 4.1-4.8 (3H, m),6.6-7.8(18H, m)

Production Example III-2

[0392] In a mixed solvent of 4 ml of tetrahydrofuran and 1.5 ml ofhexane is suspended 1 g of(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronic acid and then0.24 g of diethanolamine is added to the suspension, after which theresulting mixture is stirred for 20 minutes. The deposits are collectedby filtration to obtain 0.88 g of colorless crystals of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane.

[0393]8 α]_(D)+57.2° (25° C., c=0.33, CHCl₃)

[0394] IR (KBr) cm⁻¹: 1490, 1446

[0395] NMR (CDCl₃) δ value: 1.18(3H, d, J=6.1 Hz), 2.4-4.6 (12H, m),6.5-7.8(18H, m)

Production Example III-3

[0396] In a mixed solvent of 2 ml of water and 5 ml of ethyl acetate issuspended 1.34 g of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocaneand to this suspension are added 1.0 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,0.55 g of sodium carbonate and 0.05 g ofbis(triphenylphosphine)palladium(II) chloride, after which the resultingmixture is heated under reflux for 3 hours in a nitrogen atmosphere. Thereaction mixture is added to a mixed solvent of 10 ml of methylenechloride and 10 ml of water and the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, after which the solvent is removedfrom the layer by distillation under reduced pressure. The residueobtained is recrystallized from ethanol to obtain 1.55 g of ethyl1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

[0397] [α]_(D)+32° (27° C., c=1.0, CHCl₃)

[0398] IR (KBr) cm⁻¹; ν_(c=o) 1734, 1690

[0399] NMR (CDCl₃) δ value: 0.8-1.9(10H, m), 3.9-4.9(6H, m), 5.51(1H, t,J=75 Hz), 6.7-8.0(19H, m), 8.35(1H, d, J=8.0 Hz), 8.66(1H, s)

Reference Example IV-1

[0400] To a mixed solvent of 193.3 g of bromine and 600 ml of methylenechloride is dropwise added 176.1 g of tert-butylamine at −20° C. over 1hour and the resulting mixture is stirred at the same temperature for 1hour, after which 100.0 g of ethyl m-hydroxybenzoate is added to themixture in 5 portions. The resulting mixture is stirred at the sametemperature for 2 hours, then at 0° C. for 1 hour and further at roomtemperature for 10 hours. The deposited matters are collected byfiltration and to the matters obtained are added 500 ml of ethyl acetateand 300 ml of 6 moles/liter hydrochloric acid, and the organic layer isseparated. The organic layer is washed with saturated saline and thendried over anhydrous magnesium sulfate, and the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bydistillation under reduced pressure (135-142° C./0.5 mmHg) to obtain121.0 g of a colorless oily product of ethyl2,4-dibromo-3-hydroxybenzoate.

[0401] IR (KBr) cm⁻¹: ν_(c=o) 1722

[0402] NMR (CDCl₃) δ value: 1.40(3H, t, J=7.1 Hz), 4.40(2H, q, J=7.1Hz), 6.39(1H, brs), 7.26(1H, d, J=8.3 Hz), 7.52 (1H, d, J=8.3 Hz)

EXAMPLE IV-1

[0403] To a mixed solution of 400 ml of a 35% aqueous sodium hydroxidesolution and 49.8 g of tetrabutylammonium bromide is added a solution of100.0 g of ethyl 2,4-dibromo-3-hydroxybenzoate in 400 ml of toluene andthereafter 53.4 g of chlorodifluoromethane is blown into the resultingmixture at room temperature over 1 hour. To the reaction mixture isadded 400 ml of water and the organic layer is separated. The organiclayer obtained is washed with saturated saline and then dried overanhydrous magnesium sulfate, and the solvent is removed by distillationunder reduced pressure. The residue obtained is purified by a columnchromatography [eluant; n-hexane:ethyl acetate=10:1] to obtain 110.8 gof colorless crystals of ethyl 2,4-dibromo-3-difluoromethoxybenzoate.

[0404] IR (KBr) cm⁻¹: ν_(c=o) 1727

[0405] NMR (CDCl₃) δ value: 1.41(3H, t, J=7.1 Hz), 4.41(2H, q, J=7.1Hz), 6.65(1H, t, J=74.0 Hz), 7.48(1H, d, J=8.3 Hz), 7.66(1H, d, J=8.3Hz)

EXAMPLE IV-2

[0406] In 10 ml of N,N-dimethylformamide is dissolved 10.0 g of ethyl2,4-dibromo-3-hydroxybenzoate and to the solution are added 4.5 g ofpotassium carbonate and then 100 ml of an N,N-dimethylformamide solutionof chloro-difluoromethane (10 M solution), after which the resultingmixture is stirred at 120-130° C. for 3 hours in a sealed tube. Thereaction mixture is added to a mixed solvent of 100 ml of ethyl acetateand 100 ml of water, and the pH is adjusted to 2 with 6 moles/literhydrochloric acid, after which the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, and the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bya column chromatography [eluant; n-hexane:ethyl acetate=4:1] to obtain10.8 g of colorless crystals of ethyl2,4-dibromo-3-difluoromethoxybenzoate.

[0407] IR (KBr) cm⁻¹: ν_(c=o) 1717

[0408] NMR (CDCl₃) δ value: 6.68(1H, t, J=74.0 Hz), 7.60-7.90(2H, m),8.83(1H, brs)

EXAMPLE IV-3

[0409] In 600 ml of methylene chloride is dissolved 100.0 g of2,4-dibromo-3-difluoromethoxybenzoic acid and thereto are added 21.6 gof imidazole and 96.5 g of triethylamine, after which 37.8 g of thionylchloride is added to the resulting mixture with ice-cooling. Theresulting mixture is stirred at the same temperature for 30 minutes andfurther at room temperature for 1 hour. Subsequently, 27.5 g ofmagnesium chloride, 29.3 g of triethylamine, 98.4 g of potassiummonoethyl malonate and 100 ml of N,N-dimethylformamide are addedsuccessively to the mixture and the resulting mixture is heated underreflux for 6 hours. To the reaction mixture is added 600 ml of water andthe pH is adjusted to 1 with 6 moles/liter hydrochloric acid, afterwhich the organic layer is separated. The organic layer obtained iswashed successively with a saturated aqueous sodium hydrogen-carbonatesolution, water and saturated saline, and thereafter, dried overanhydrous magnesium sulfate, after which the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bya column chromatography [eluant; n-hexane:ethyl acetate=20:1] to obtain108.2 g of colorless crystals of ethyl2,4-dibromo-3-difluoromethoxybenzoyl acetate.

[0410] IR (KBr) cm⁻¹: ν_(c=o) 1670

[0411] NMR (CDCl₃) δ value: 1.25(1.8H, t, J=7.1 Hz), 1.34 (1.2H! t,J=7.1 Hz), 3.98(1.2H, s), 4.19(1.2H, q, J=7.1 Hz), 4.29(0.8H, q, J=7.1Hz), 5.40(0.4H, s), 6.65(1H, t, J=73.7 Hz), 7.25(1H, d, J=8.3 Hz),7.65(0.6H, d, J=8.3 Hz), 7.69(0.4H, d, J=8.3 Hz), 12.41(0.4H, s)

EXAMPLE IV-4

[0412] In 600 ml of methylene chloride is dissolved 100.0 g of ethyl2,4-dibromo-3-difluoromethoxybenzoylacetate and to the solution areadded 31.9 g of acetic anhydride and 37.2 g of N,N-dimethylformamidedimethyl acetal, after which the resulting mixture is stirred at roomtemperature for 1 hour and the solvent is removed by distillation underreduced pressure. The residue obtained is dissolved in 500 ml ofisopropanol, and 14.8 g of cyclopropylamine is added thereto, afterwhich the resulting mixture is stirred at room temperature for 1 hour.The crystals deposited are collected by filtration to obtain 95.2 g ofcolorless crystals of ethyl2-(2,4-dibromo-3-difluoromethoxybenzoyl)-3-cyclopropylaminoacrylate.

[0413] IR (KBr) cm⁻¹: ν_(c=o) 1675, 1621

[0414] NMR (CDCl₃) δ value: 0.60-1.20(7H, m), 2.80-3.20(1H, m), 3.96(2H,q, J=7.1 Hz), 6.61(1H, t, J=7.40 Hz), 6.92(1H, d, J=8.3 Hz), 7.58(1H, d,J=8.3 Hz), 8.28(0.8H, d, J=13.9 Hz), 8.37(0.2H, d, J=13.9 Hz),9.60-9.90(0.2H, m), 10.80-11.30(0.8H, m)

EXAMPLE IV-5

[0415] In 400 ml of dimethyl sulfoxide is dissolved 100.0 g of ethyl2-(2,4-dibromo-3-difluoromethoxybenzoyl)-3-cyclopropylaminoacrylate andthen 34.3 g of potassium carbonate is added thereto, after which theresulting mixture is stirred at 90° C. for 2 hours. The reaction mixtureis cooled to room temperature and thereafter 800 ml of water is addedthereto, after which the crystals deposited are collected by filtrationto obtain 78.3 g of colorless crystals of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate.

[0416] IR (KBr) cm⁻¹: ν_(c=o) 1687, 1640

[0417] NMR (CDCl₃) δ value: 0.70-1.70(7H, m), 3.70-4.70(3H, m), 6.52(1H,t, J=74.5 Hz), 7.58(1H, d, J=8.5 Hz), 8.24(1H, d, J=8.5 Hz), 8.59(1H, s)

Production Example IV-1

[0418] In 15 ml of ethanol is dissolved 2.5 g of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,and thereto are added 2.8 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylateand 1.1 g of sodium carbonate. Subsequently, 150 mg of 10%palladium-activated carbon is added to the mixture in a nitrogenatmosphere and thereafter the resulting mixture is heated under refluxfor 3 hours in the same atmosphere. The reaction mixture is cooled andthereafter added to a mixed solvent of 15 ml of water and 30 ml ofacetone, and the crystals deposited are collected by filtration toobtain 3.6 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

Production Example IV-2

[0419] In 68 ml of conc. hydrochloric acid is suspended 34 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate,and the suspension is heated under reflux for 3 hours, after which 340ml of water is added to the resulting mixture and 170 ml of the solventis removed from the mixture by distillation under atmospheric pressureover 3 hours. The reaction mixture is cooled and thereafter 17 ml ofethanol is added to the mixture, after which the crystals deposited arecollected by filtration. The resulting(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride is suspended in 340 ml of water and the pH of themixture is adjusted to 7.5 with 2 moles/liter sodium hydroxide solution,after which the crystals deposited are collected by filtration to obtain25.55 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid monohydrate.

Production Example IV-3

[0420] In 192 ml of 50% ethanol is suspended 24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid monohydrate, and the suspension is warmed to 40° C., after which5.71 g of methanesulfonic acid is added to form a uniform solution.Subsequently, 2.4 g of activated carbon is added and the resultingmixture is stirred at the same temperature for 10 minutes, after whichthe insolubles are removed by filtration. The filtrate is concentratedand the crystals deposited are collected by filtration to obtain 26.64 gof(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.

EXAMPLE V-1

[0421] In 192 ml of 50% water-containing ethanol is suspended 24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is warmed to 40° C., after which 5.71 g ofmethanesulfonic acid is added to the warmed suspension to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 10 minutes and thereafter filtered, and the filtrate isconcentrated, after which the crystals deposited are collected byfiltration to obtain 26.64 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.

[0422] IR (KBr) cm⁻¹: ν_(c=o) 1724, 1615

[0423] NMR (TFA-d) δ value: 1.2-2.1(7H, m), 3.16(3H, s), 4.7-5.7(4H, m),6.21(1H, t, J=72 Hz), 7.5-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.78(1H, d,J=10 Hz), 9.66 (1H, s)

[0424] Water content: 3.31%

EXAMPLE V-2

[0425] In 4 ml of ethanol is suspended 0.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and then the suspension is warmed to 70° C., after which 45 mg ofmethanesulfonic acid is added to the warmed suspension to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 1 hour and then cooled to room temperature, after which the crystalsdeposited are collected by filtration to obtain 0.20 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate.

[0426] IR(KBr) cm⁻¹: ν_(c=o) 1716, 1613

[0427] NMR (TFA-d) δ value: 1.2-2.1(7H, m), 3.16(3H, s), 4.6-5.6(4H, m),6.21(1H, t, J=73 Hz), 7.4-8.0(3H, m), 8.17(1H, d, J=10 HZ), 8.80(1H, d,J=10 Hz), 9.66(1H, s)

[0428] Water content: 0.1%

EXAMPLE V-3

[0429] In 2 ml of ethanol is suspended 0.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate and the suspension is stirred at roomtemperature for 15 hours, and then subjected to collection by filtrationto obtain 0.14 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate.

[0430] The physical property values of the compound obtained above wereidentical with those of the compound obtained in Example V-2.

[0431] Water content: 0.33%

Reference Example V-1

[0432] In 10 ml of 50% water-containing ethanol is suspended 0.5 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is warmed to 50° C., after which 0.14 g ofphosphoric acid is added to the warmed suspension to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 10 minutes and then subjected to filtration. The filtrate is cooledto room temperature and then the crystals deposited are collected byfiltration to obtain 0.32 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid phosphate.

[0433] IR (KBr) cm⁻¹: ν_(c=o) 1722, 1616

[0434] NMR (TFA-d) δ value: 1.1-2.1(7H, m), 4.5-5.6(4H, m), 6.20(1H, t,J=75 Hz), 7.4-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.80(1H, d, J=10 Hz),9.65(1H, s)

Reference Example V-2

[0435] In 8.2 ml of 40% water-containing ethanol is suspended 0.7 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicand then 0.16 g of L-lactic acid is added thereto, after which theresulting mixture is warmed to 50° C. to form a uniform solution.Subsequently, the solution is subjected to filtration at the sametemperature and the filtrate is thereafter concentrated, and thecrystals deposited are collected by filtration to obtain 0.57 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid L-lactate.

[0436] IR (KBr) cm⁻¹: ν_(c=o) 1723, 1616

[0437] NMR (TFA-d) δ value: 1.2-2.1(10H, m), 4.4-5.6(5H, m), 6.19(1H, t,J=72 Hz), 7.5-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.79(1H, d, J=10 Hz),9.64(1H, s)

Reference Example V-3

[0438] In 9.4 ml of 25% water-containing ethanol is suspended 1.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid, and 2.57 ml of 1 mole/liter aqueous sodium hydroxide solution isadded thereto, after which the resulting mixture is exposed toultrasonic wave for 1 hour to form a uniform solution. Subsequently, thereaction mixture is washed twice with chloroform, and concentrated, andthe crystals deposited are collected by filtration to obtain 0.49 g ofsodium(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

[0439] IR (KBr) cm⁻¹: ν_(c=o) 1636

[0440] NMR (TFA-d) δ value: 1.2-2.1(7H, m), 4.6-5.6(4H, m), 6.20(1H, t,J=72 Hz), 7.5-8.0(3H, m), 8.17(1H, d, J=10 Hz), 8.79(1H, d, J=10 Hz),9.66(1H, s)

Reference Example V-4

[0441] In 42 ml of 50% water-containing ethanol is suspended 0.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and 0.11 g of citric acid is then added thereto, after which theresulting mixture is warmed to 65° C. to form a uniform solution.Subsequently, the solution is filtered at the same temperature and thefiltrate is concentrated, after which the crystals deposited arecollected by filtration to obtain 0.24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid citrate.

[0442] IR (KBr) cm⁻¹: ν_(c=o) 1724, 1616

Reference Example V-5

[0443] In 0.75 ml of acetic acid is suspended 0.5 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is warmed to 80° C. to form a uniform solution.Subsequently, the solution is filtered at the same temperature and then2.5 ml of ethanol is added to the filtrate, after which the crystalsdeposited are collected by filtration to obtain 0.24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid acetate.

[0444] IR (KBr) cm⁻¹: ν_(c=o) 1723, 1622

[0445] NMR (TFA-d) δ value: 1.2-2.1(7H, m), 2.28(3H, s), 4.7-5.6(4H, m),6.20(1H, t, J=74 Hz), 7.5-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.80(1H, d,J=10 Hz), 9.64(1H, s)

Reference Example V-6

[0446] In 20 ml of 50% water-containing ethanol is suspended 1.0 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is then warmed to 50° C., after which 0.41 ml of6 moles/liter hydrochloric acid is added thereto to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 10 minutes and then filtered. The filtrate is cooled to roomtemperature and the crystals deposited are thereafter collected byfiltration to obtain 0.56 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride.

[0447] IR (KBr) cm⁻¹: ν_(c=o) 1722, 1616

[0448] NMR (TFA-d) δ value: 1.2-2.1(7H, m), 4.5-5.6(4H, m), 6.21(1H, t,J=73 Hz), 7.5-8.0(3H, m), 8.15(1H, d, J=10 Hz), 8.78(1H, d, J=10 Hz),9.65(1H, s)

Reference Example V-7

[0449] In 12 ml of 20% water-containing ethanol is suspended 0.6 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-1(-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and 74 mg of magnesium ethoxide is then added thereto, after whichthe resulting mixture is heated under reflux for 2 hours. Subsequently,the reaction mixture is cooled to room temperature and thereafter thecrystals are collected by filtration to obtain 0.55 g of magnesium saltof(R)-l-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid.

[0450] IR (KBr) cm⁻¹: ν_(c=o) 1612

[0451] NMR (TFA-d) δ value: 1.1-2.1(7H, m), 4.5-5.6(4H, m), 6.20(1H, t,J=73 Hz), 7.5-8.0(3H, m), 8.12(1H, d, J=10 Hz), 8.78(1H, d, J=10 Hz),9.65(1H, s)

Reference Example V-8

[0452] In 10 ml of 50% water-containing ethanol is suspended 0.5 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is then warmed to 50° C., after which 0.12 g ofsulfuric acid is added thereto to form a uniform solution. Subsequently,the solution is stirred at the same temperature for 10 minutes and thenfiltered. The filtrate is cooled to room temperature and thereafter thecrystals deposited are collected by filtration to obtain 0.34 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid sulfate.

[0453] IR (KBr) cm⁻¹: ν_(c=o) 1724, 1615

[0454] NMR (TFA-d) δ value: 1.2-2.1(7H, m), 4.6-5.6(4H, m), 6.20(1H, t,J=73 Hz), 7.5-8.0(3H, m), 8.12(1H, d, J=10 Hz), 8.80(1H, d, J=10 Hz),9.65(1H, s)

Preparation Example V-1

[0455] 380.4 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate, 83.1 g of lactose, 36 g of cornstarch and 27 g of carboxymethyl starch sodium (Primojel, MatsutaniKagaku) are mixed, and the mixture is thereafter introduced into akneader (small size bench kneader, Koike Tekko) and then kneaded while180 g of a 6% aqueous hydroxypropyl cellulose solution (HPC-L, NipponSoda) is gradually added. The kneaded product is subjected to sizereduction by a power mill (PS-04S, Dalton, 2-mm herringbone screen) andthen dried by blowing air at 40° C. overnight. After the drying, theproduct is subjected to size reduction by a power mill (20-mesh squarescreen), and thereafter, 2.7 g of magnesium stearate is added theretoand mixed therewith to prepare a powder for tableting. This powder istableted by a rotary type tablet machine (HP-18, Hata Tekko) using apunch having a diameter of 7.5 mm so that the weight of one tabletbecomes 180 mg to obtain tablets each containing 100 mg of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (as free base). This tablet is subjected to film coating in anaqueous system by conventional procedure (4 mg of hydroxypropylmethylcellulose (TC-5), 0.8 mg of Macrogol 6000, 0.4 mg of titanium oxide and0.4 mg of talc per tablet) to obtain a film-coated tablet.

Preparation Example V-2

[0456] Into 958 g of water for injection is introduced 6.338 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate while stirring to dissolve the latterin the former. To the solution are added 0.62 ml of 0.1 mole/litermethanesulfonic acid and 50 g of D-mannitol and the resulting mixture isfurther stirred. After the complete dissolution, the solution isfiltered through a 0.22-μm membrane filter. This filtrate is chargedinto vials in a proportion of 100 ml per vial and each of the vials isstopped with a rubber compound stopper and an aluminum cap andthereafter subjected to steam sterilization (121° C., 20 minutes) toobtain injections, each vial containing 500 mg of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (as free base).

Industrial Applicability

[0457] The production process of this invention is useful as a processfor the industrial production of a 7-isoindoline-quinolonecarboxylicacid derivative useful as an antibacterial agent, particularly T-3811and isoindoline-5-boronic acid derivatives, 1-alkylisoindoline-5-boronicacid derivatives, 1-alkyl-5-halogenoisoindoline derivatives and7-bromo-quinolonecarboxylic acid derivatives which are intermediates forT-3811.

[0458] Moreover, T-3811 methanesulfonate is remarkably high insolubility at a physiologically acceptable pH and further T-3811methanesulfonate monohydrate has no polymorphism and is good instability against humidity and hence useful as the starting material fora composition comprising T-3811 as an active ingredient, particularlyfor a T-3811 preparation.

1. A process for producing a 7-isoindolinequinolonecarboxylic acidderivative or its salt, characterized in that the process for producinga compound represented by the general formula [1]:

wherein R¹ represents a hydrogen atom or a carboxyl-protecting group; R²represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,aryl or heterocyclic group; R³ represents at least one group selectedfrom hydrogen atom, halogen atoms, substituted or unsubstituted alkyl,alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group,cyano group, acyl groups, protected or unprotected hydroxyl groups andprotected or unprotected or substituted or unsubstituted amino groups;R⁴ represents at least one group selected from hydrogen atom, halogenatom, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl,aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl orimino groups, protected or unprotected or substituted or unsubstitutedamino groups, alkylidene groups, oxo group and groups each forming acycloalkane ring together with the carbon atom to which R⁴ bonds; R⁵represents a hydrogen atom, an amino-protecting group, a substituted orunsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl oraryl group; R⁶ represents a hydrogen atom, a halogen atom, a substitutedor unsubstituted alkyl, alkoxy or alkylthio group, a protected orunprotected hydroxyl or amino group or a nitro group; and A representsCH or C-R⁷ in which R⁷ represents a halogen atom, a substituted orunsubstituted alkyl, alkoxy or alkylthio group or a protected orunprotected hydroxyl group, is either the following (i) or (ii): (i) Aprocess characterized by reacting, in the presence of metallic palladiuman isoindoline-5-boronic acid derivative represented by the followinggeneral formula [2] or its salt:

 wherein R³, R⁴ and R⁵ have the same meanings as mentioned above; and R⁸and R⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, with a 7-leavinggroup-substituted quinolonecarboxylic acid represented by the followinggeneral formula [3] or its salt:

 wherein R¹, R², R⁶ and A have the same meanings as mentioned above; andX² represents a leaving group. (ii) A process characterized by reacting,in the presence of a palladium catalyst selected from metallicpalladium, palladium salts and palladium complexes, a5-halogenoisoindoline derivative represented by the following generalformula [4] or its salt:

 wherein R³, R⁴ and R⁵ have the same meanings as mentioned above; and X¹represents a halogen atom, with a dialkoxyborane represented by thegeneral formula [5a]:

 wherein Z represents an alkylene group, or an alkoxydiboranerepresented by the general formula [5b]:

 wherein Z has the same meaning as mentioned above, to form anisoindoline-5-boronic acid derivative represented by the followinggeneral formula [2a] or its salt:

 wherein R³, R⁴, R⁵ and Z have the same meanings as mentioned above; andthereafter, reacting the isoindoline-5-boronic acid derivative or itssalt without isolation with a 7-leaving group-substitutedquinolonecarboxylic acid represented by the following general formula[3] or its salt:

 wherein R¹, R², R⁶, A and X² have the same meanings as mentioned above.2. A process for producing a 7-isoindolinequinolonecarboxylic acidderivative or its salt according to claim 1, wherein R⁵ represents ahydrogen atom, a substituted or unsubstituted alkyl, cycloalkyl,alkylsulfonyl, arylsulfonyl, acyl or aryl group.
 3. A process forproducing an isoindoline-5-boronic acid derivative represented by thefollowing general formula [2a] or its salt:

wherein R³ represents at least one group selected from hydrogen atom,halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl,aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups,protected or unprotected hydroxyl groups and protected or unprotected orsubstituted or unsubstituted amino groups; R⁴ represents at least onegroup selected from hydrogen atom, halogen atoms, substituted orunsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy oralkylthio groups, protected or unprotected hydroxyl or imino groups,protected or unprotected or substituted or unsubstituted amino groups,alkylidene groups, oxo group and groups each forming a cycloalkane ringtogether with the carbon atom to which R⁴ bonds; R⁵ represents ahydrogen atom, an amino-protecting group, a substituted or unsubstitutedalkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; andZ represents an alkylene group, characterized by reacting, in thepresence of a palladium catalyst selected from metallic palladium,palladium salts and palladium complexes, a 5-halogenoisoindolinederivative represented by the following general formula [4] or its salt:

 wherein R³, R⁴ and R⁵ have the same meanings as mentioned above; and X¹represents a halogen atom, with a dialkoxyborane represented by thegeneral formula [5a]:

 wherein Z has the same meaning as mentioned above, or an alkoxydiboranerepresented by the general formula [5b]:

 wherein Z has the same meaning as mentioned above.
 4. A process forproducing an isoindoline-5-boronic acid derivative or its salt accordingto claim 3, wherein R⁵ represents a hydrogen atom, a substituted orunsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl oraryl group.
 5. A process for producing a 1-alkylisoindoline-5-boronicacid derivative represented by the general formula [2b] or its salt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R⁸ andR⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, characterized by reactinga phenylalkylamine derivative represented by the general formula [10] orits salt:

 wherein R^(4a) has the same meaning as mentioned above; and R^(5a)represents an amino-protecting group, a substituted or unsubstitutedalkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, withcarbon dioxide, a halogenated formic acid ester or a carbonic acid esterin the presence of a base to form a 2-aminoalkylbenzoic acid derivativerepresented by the general formula [9] or its salt:

 wherein R^(4a) and R⁵ have the same meanings as mentioned above; andR¹⁰ represents a hydrogen atom or a carboxyl-protecting group,subsequently subjecting the 2-aminoalkylbenzoic acid derivative or itssalt to halogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoicacid derivative represented by the general formula [8] or its salt:

 wherein R^(4a), R⁵ and R¹⁰ have the same meanings as mentioned above;and X¹ represents a halogen atom, subsequently subjecting the2-aminoalkyl-5-halogenobenzoic acid derivative or its salt to reductionreaction to obtain a 2-aminoalkyl-5-halogenobenzyl alcohol derivativerepresented by the following general formula [6] or its salt:

 wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above,and thereafter subjecting the 2-aminoalkyl-5-halogenobenzyl alcoholderivative or its salt to ring-closing reaction to obtain a1-alkyl-5-halogenoisoindoline derivative represented by the generalformula [4a] or its salt:

 wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above andthen subjecting the 1-alkyl-5-halogenoisoindoline derivative or its saltto borodation.
 6. A process for producing a 1-alkylisoindoline-5-boronicacid derivative or its salt according to claim 5, wherein R^(4a)represents a lower alkyl group; R^(5a) represents an amino-protectinggroup; and R⁵ represents a hydrogen atom or an amino-protecting group.7. A process for producing a 1-alkylisoindoline-5-boronic acidderivative represented by the general formula [2b] or its salt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R⁸ andR⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, characterized by reactinga phenylalkylamine derivative represented by the general formula [10] orits salt:

 wherein R^(4a) has the same meaning as mentioned above; and R^(5a)represents an amino-protecting group, a substituted or unsubstitutedalkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, withcarbon dioxide, a halogenated formic acid ester or a carbonic acid esterin the presence of a base, to obtain a 2-aminoalkylbenzoic acidderivative represented by the general formula [9] or its salt:

 wherein R^(4a) and R⁵ have the same meanings as mentioned above; andR¹⁰ represents a hydrogen atom or a carboxyl-protecting group,subsequently subjecting the 2-aminoalkylbenzoic acid derivative or itssalt to halogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoicacid derivative represented by the general formula [8] or its salt:

 wherein R^(4a), R⁵ and R¹⁰ have the same meanings as mentioned above;and X¹ represents a halogen atom, subsequently subjecting the2-aminoalkyl-5-halogenobenzoic acid derivative or its salt toring-closing reaction to obtain a 1-alkyl-3-oxo-5-halogenoisoindolinederivative represented by the general formula [7] or its salt:

 wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above,subsequently subjecting the 1-alkyl-3-oxo-5-halogenoisoindolinederivative or its salt to reduction reaction to obtain a1-alkyl-5-halogenoisoindoline derivative represented by the generalformula [4a] or its salt:

 wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above,and then subjecting the 1-alkyl-5-halogenoisoindoline derivative or itssalt to borodation.
 8. A process for producing a1-alkylisoindoline-5-boronic acid derivative or its salt according toclaim 7, wherein R^(4a) represents a lower alkyl group; R^(5a)represents an amino-protecting group; and R⁵ represents a hydrogen atomor an amino-protecting group.
 9. A process for producing a1-alkyl-5-halogenoisoindoline derivative represented by the generalformula [4a] or its salt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and X¹represents a halogen atom, by reacting a 4-halogenobenzylaminederivative represented by the general formula [12] or its salt:

 wherein R^(4a) and X¹ have the same meanings as mentioned above; andR^(5b), R^(5c) and R^(5d) may be the same or different and eachrepresents an alkyl group, with a formaldehyde or its derivative in thepresence of an aryllithium to obtain a 2-aminoalkyl-5-halogenobenzylalcohol derivative represented by the general formula [6] or its salt:

 wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above,subsequently introducing a leaving group thereinto to obtain a2-aminoalkyl-5-halogenobenzyl derivative represented by the generalformula [11] or its salt:

 wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above;and Y represents a leaving group, and subsequently subjecting the2-aminoalkyl-5-halogenobenzyl derivative to ring-closing reaction in thepresence of a base.
 10. A process for producing a1-alkyl-5-halogenoisoindoline derivative or its salt according to claim9, wherein R⁵ represents a hydrogen atom or an amino-protecting group.11. A process for producing a 7-bromoquinolonecarboxylic acid derivativerepresented by the general formula [3a] or its salt:

wherein R^(1b) represents a carboxyl-protecting group; R^(2a) representsa substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclicgroup; and R^(7a) represents a substituted or unsubstituted alkyl group,characterized by reacting a 2,4-dibromo-3-hydroxybenzoic acid esterrepresented by the general formula [13] or its salt:

 wherein R^(1a) represents a carboxyl-protecting group, with a compoundrepresented by the general formula [14]: R^(7a)-X  [14]  wherein R^(7a)has the same meaning as mentioned above; and X represents a halogenatom, to obtain a 3-alkoxy-2,4-dibromobenzoic acid ester represented bythe general formula [15] or its salt:

 wherein R^(1a) and R^(7a) have the same meanings as mentioned above,subsequently subjecting the 3-alkoxy-2,4-dibromobenzoic acid ester toelimination reaction of the carboxyl-protecting group to obtain a3-alkoxy-2,4-dibromobenzoic acid represented by the general formula [16]or its salt:

 wherein R^(7a) has the same meaning as mentioned above, subsequentlysubjecting the 3-alkoxy-2,4-dibromobenzoic acid to ketoesterificationreaction to obtain a 3-alkoxy-2,4-dibromobenzoylacetic acid esterrepresented by the general formula [17] or its salt:

 wherein R^(1b) represents a carboxyl-protecting group; and R^(7a) hasthe same meaning as mentioned above, subsequently reacting the3-alkoxy-2,4-dibromobenzoylacetic acid ester with an orthoester or anacetal, then reacting the reaction product with a compound representedby the general formula [18] or its salt: R^(2a)—NH  [18]  wherein R^(2a)has the same meaning as mentioned above, to obtain a2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid esterrepresented by the general formula [19] or its salt:

 wherein R^(1b), R^(2a) and R^(7a) have the same meanings as mentionedabove, and thereafter subjecting the2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester toring-closing reaction. 12.(R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate. 13.(R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.
 14. A composition comprising anactive ingredient selected from the group consisting of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate and(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate, and an inactive ingredient.
 15. Thecomposition according to claim 14, wherein the inactive ingredient is acarrier acceptable as a preparation.
 16. An isoindolin-5-ylboronic acidderivative represented by the general formula [2a] or its salt:

wherein R³ represents at least one group selected from hydrogen atom,halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl,aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups,protected or unprotected hydroxyl groups and protected or unprotected orsubstituted or unsubstituted amino groups; R⁴ represents at least onegroup selected from hydrogen atom, halogen atoms, substituted orunsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy oralkylthio groups, protected or unprotected hydroxyl or imino groups,protected or unprotected or substituted or unsubstituted amino groups,alkylidene groups, oxo group and groups each forming a cycloalkane grouptogether with the carbon atom to which R⁴ bonds; R⁵ represents ahydrogen atom, an amino-protecting group, a substituted or unsubstitutedalkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; andZ represents an alkylene group.
 17. A 2-aminoalkyl-5-halogenobenzylalcohol derivative represented by the general formula [6] or its salt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and X¹represents a halogen atom.
 18. A process for producing a7-isoindolinequinolonecarboxylic acid derivative or its salt accordingto claim 1, wherein the compound represented by the general formula [2]or its salt is a compound represented by the general formula [2b] or itssalt obtained by the process according to claim 5, the compoundrepresented by the general formula [3] or its salt is a compoundrepresented by the general formula [3b] or its salt, and the compoundrepresented by the general formula [1] or its salt is a compoundrepresented by the general formula [1a] or its salt.
 19. A process forproducing a 7-isoindolinequinolonecarboxylic acid derivative or its saltaccording to claim 1, wherein the compound represented by the generalformula [2] or its salt is a compound represented by the general formula[2b] or its salt obtained by the process according to claim 7, thecompound represented by the general formula [3] or its salt is acompound represented by the general formula [3b] or its salt, and thecompound represented by the general formula [1] or its salt is acompound represented by the general formula [1a] or its salt.
 20. Aprocess for producing a 7-isoindolinequinolonecarboxylic acid derivativeor its salt according to claim 1, wherein the compound represented bythe general formula [2] or its salt is a compound represented by thegeneral formula [2b] or its salt obtained by preparing a compoundrepresented by the general formula [4a] or its salt by the processaccording to claim 9 and subjecting the compound represented by thegeneral formula [4a] or its salt to borodation, and the compoundrepresented by the general formula [1] or its salt is a compoundrepresented by the general formula [1a] or its salt.
 21. A process forproducing a 7-isoindolinequinolonecarboxylic acid derivative or its saltaccording to claim 1, wherein the compound represented by the generalformula [3] or its salt is a compound represented by the general formula[3a] or its salt obtained by the process according to claim 11, and thecompound represented by the general formula [1] or its salt is acompound represented by the general formula [1b] or its salt.